MX2009000486A - 4-amino-4-oxobutanoyl peptides as inhibitors of viral replication. - Google Patents

Abstract

The invention rovides 4-amino-4-oxobutanoyl peptide compounds of FormulaI (I) and the pharmaceutically salts and hydrates thereof. The variables R1-R9,R16, R18 R19, n, M,, n, M,, and Z are defined herein. Certain compounds of FormulaI are useful as antiviral agents. Certain 4-amino-4-oxobutanoyl peptide compoundsdisclosed herein are potent and/ or selective inhibitors of viral replication,particularly Hepatitis C virus replication. The invention also provides pharmaceuticalcompositions containing one or more 4-amino-4-oxobutanoyl peptide compoundsand one or more pharmaceutically acceptable carriers. Such pharmaceuticalcompositions may contain 4-amino-4-oxobutanoyl peptide compound as the onlyactive agent or may contain a combination of 4-amino-4-oxobutanoyl peptidecontaining peptides compound and one or more other pharmaceutically activeagents. The invention also provides methods for treating viral infections,including Hepatitis C infections, in mammals.

Description

PEPTIDES OF 4-AMINO-4-OXOBUTANOILO AS INHIBITORS OF VIRAL REPLICATION Cross reference to related applications This application claims priority over US provisional patent applications numbers 60/830, 488, filed July 1, 2006 and 60 / 945,786, filed on June 22, 2007, both incorporated herein by reference In its whole . FIELD OF THE INVENTION The present invention provides 4-amino-4-oxobutanoyl peptides, useful as antiviral agents. Some 4-amino-4-oxobutanoyl peptides described herein are potent and / or selective inhibitors of viral replication, particularly of the replication of the Hepatitis C virus. The invention also provides pharmaceutical compositions containing one or more peptides of 4- amino-4-oxobutanoyl and one or more pharmaceutically acceptable carriers, excipients, or diluents. These pharmaceutical compositions may contain 4-amino-4-oxobutanoyl peptide as the sole active agent or may contain a combination of a 4-amino-4-oxobutanoyl peptide or related compound and one or more other pharmaceutically active agents. The invention also provides methods for treating viral infections, including Hepatitis C infections, in mammals. BACKGROUND OF THE INVENTION It is estimated that 3% of the world population is infected with the hepatitis C virus. Of those exposed to HCV, 80% become chronically infected, at least 30% develop liver cirrhosis and 1-4% develop hepatocellular carcinoma. The hepatitis C virus (HCV) is one of the most prevalent causes of chronic liver disease in the United States, which according to reports constitutes approximately 1 5 percent of acute viral hepatitis, 60 to 70 percent of the chronic hepatitis and up to 50 percent of cirrhosis, end-stage liver disease, and liver cancer. Chronic HCV infection is the most common cause of liver transplantation in the United States, Australia, and most European countries. Hepatitis C produces an estimated 10,000 to 1,200,000 deaths annually in the United States. While the acute phase of HCV infection is usually associated with mild symptoms, some evidence suggests that only about 15% to 20% of infected people will eliminate HCV. HCV is a enveloped single-stranded RNA virus, containing a positive strand genome of approximately 9.6 Kb. HCV is classified as a member of the Hepacivirus genus of the Flaviviridae family. At least 4 strains of HCV, GT- to GT-4, have been characterized. The life cycle of HCV includes entry into host cells, translation of the HCV genome, processing of polyprotein and assembly of the replicase complex, replication of the DNA, and assembly and release of the virion. The translation of the HCV RNA genome produces a polyprotein of more than 3000 amino acids in length that is processed by at least two cellular proteases and two viral proteases. The HCV polyprotein is: NH2-C-E 1 -E2-p7-NS2-NS3-NS4A-NS4B-NS5A-NS5B-COO H. The cellular peptidase signal and the signal peptidase peptidase have been reported as responsible for the division of the third N-terminus of the polyprotein (EC1-E2-p7) of the non-structural proteins (NS2-NS3-NS4A-NS4B-NS5A-NS5B) . The NS2-NS3 protease mediates a first cis division at the NS2-NS3 site. The NS3-NS4A protease then mediates a second cis division at the junction of NS3-N S4 A. Then the NS3-NS4A complex is divided into three downstream sites to separate the remaining nonstructural proteins. It is ensured that the precise processing of the polyprotein is essential to form an HCV replicase active complex. Once the polyprotein has been divided, the replicase complex containing at least the non-structural proteins N S3-NS5B is assembled. The replicase complex is cytoplasmic and membrane-associated. The main enzymatic activities in the replicase complex include serine protease activity and NTPase helicase activity in NS3, and RNA-dependent RNA polymerase activity of NS5B. In the process of RNA replication, a complementary copy of the negative chain of genomic RNA is produced. The copy of the negative string is used as a template to synthesize other positive chain genomic RNAs that can participate in translation, replication, packaging or in any combination of them to produce a progeny virus. The assembly of a functional replicase complex has been described as a component of the mechanism of HCV replication. Provisional Application 60 / 669,872"Pharmaceutical Compositions and Methods for Inhibiting HCV Replication" filed April 1, 2005, is hereby incorporated by reference in its entirety by its description relating to the entire replicase complex. Current treatment of Hepatitis C infection commonly includes administration of an interferon, such as pegylated interferon (I FN), in combination with ribavirin. The success of current therapies measured by the prolonged virological response (SVR) depends on the strain of HCV with which the patient is infected and the patient's adherence to the treatment regimen. Only 50% of patients infected with the HCV strain GT-1 have a prolonged virological response. Direct acting antiviral agents such as ACH-806, VX-950 and NM 283 (prodrug of NM 107) are in clinical development for the treatment of chronic infection with HCV. Due to the lack of effective therapies for the treatment of certain strains of HCV and the high mutation rate of VHC, new therapies are necessary. The present invention satisfies this need and provides additional advantages, which are described herein.

Brief Description of the Invention The invention provides compounds of Formula I (shown below) and includes 4-amino-4-oxobutanoyl peptides and related compounds. Some 4-amino-4-oxobutanoyl peptides described herein possess antiviral activity. The invention provides compounds of Formula I which are potent and / or selective replication inhibitors of Hepatitis C virus. The invention also provides pharmaceutical compositions containing one or more compounds of Formula I, or a salt, solvate or acylated prodrug of these compounds, and one or more pharmaceutically acceptable carriers, excipients, or diluents. The invention further comprises methods for treating patients suffering from some infectious diseases, by providing these patients with an amount of a compound of Formula I effective to reduce the signs or symptoms of an infectious disease, but also comprising methods of treating others. animals, including livestock and pets, that suffer from an infectious disease. Methods of treatment include providing a compound of Formula I as a single active agent or providing a compound of Formula I in combination with one or more other therapeutic agents. Thus, in a first aspect, the invention includes compounds of Formula I and pharmaceutically acceptable salts thereof: (Formula I) In Formula I the variables, for example R1-R9, Laugh, Laugh. 19, M, Y, Z, and n, carry the definitions that are discussed below. . represents a single or double covalent bond, and the group 0 or 1 double links.

R1 is -NR10Rii, 1, - (C = 0) R12, -SO2R12, - (C = 0) OR12, -0 (C = 0) R12, -OR12, or -N (C = 0) R12) and R2 is hydrogen, C ^ -Cealkyl, C3-C7cycloalkyl, heterocycloalkyl, (aryl) C0-C4alkyl; or R1 and R2 are taken together to form an optionally substituted 5 to 7 membered heterocyclic ring containing 0 or 1 additional N, S or O atoms, or an optionally substituted 5 to 7 membered heterocyclic ring containing 0 or 1 atoms additional N, S or O fused with a 5- or 7-membered carbocyclic or heterocyclic ring optionally substituted.

F * 3, R4, 5. R6. R7 and independently are (a) hydrogen, halogen or amino, or (b) d-Cealkyl, C2-C6alkenyl, (C3-C7cycloalkyl) Co-C4alkyl, (C3-C7cycloalkenyl) C0-C4alkyl(C6-C4alkyl, C2-C6alkanoyl, or mono- or diCi-C6alkylamino, (heterocycloalkyl)), each of which is optionally substituted. R3 and 4 may be attached to form an optionally substituted 3 to 7-membered cycloalkyl ring or an optionally substituted 3 to 7 membered heterocycloalkyl ring containing 1 or 2 heteroatoms independently selected from N, S, and O. R5 and R6 may be linked to form an optionally substituted 3 to 7-membered cycloalkyl ring or an optionally substituted 3 to 7 membered heterocycloalkyl ring containing 1 or 2 heteroatoms independently selected from N, S, and O. R7 and R8 may be joined to form a ring optionally substituted 3 to 7 membered cycloalkyl or an optionally substituted 3 to 7 membered heterocycloalkyl ring containing 1 or 2 heteroatoms independently selected from N, S, and O. R 5 is a saturated or unsaturated hydrocarbon chain of 7 to 11 carbon atoms. carbon that is (i) covalently attached to R7, wherein R7 is a methylene group or R5 is a saturated or unsaturated hydrocarbon chain of to 11 carbon atoms that is (ii) covalently linked to an optionally substituted cycloalkyl ring, formed by R7 and R8 which are attached to form a 3- to 7-membered cycloalkyl ring optionally substituted; and R 6 is hydrogen, d-Cealkyl, or (C 3 -C 7 cycloalkyl) C 0 -C 2 alkyl; T is a tetrazole group bound via its carbon atom, or T is a group of the formula: Where R9 is hydroxyl, amino, -COOH, -NR 0R, -OR12, -SR12, -NR10SO2Rii, -NR10SONRiiR12, -NR ^ SOZNRT ·, R12, (C = O) OR10, -NR10 (C = O) OR11 > or - CONR10R, or R9 is d-Cealkyl, C2-C6alkenyl, C2-C6alkanoyl, (C3-C7cycloalkyl) Co-C4alkyl, (C3- C7cycloalkenyl) C0-C4alkyl, (C3-C7cycloalkyl) CH2S02-, (C3- C 7 Cycloalkyl) CH 2 SO 2 NR 10-, (C 1 -C 4 heterocycloalkyl) alkyl, (C aryl) C 2 -C alkyl, or C 0 -C 2 (heteroaryl of 5 to 10 members), each of which is optionally substituted. O, Rg is a phosphonate of the formula where p is 0, 1, or 2; or R9 is RxXC0-C4alkyl-, wherein X is - (C = 0) NH-, -NH (C = 0) - and Rx is aryl or heteroaryl, or R9 is -CH (RY) (C3-C7cycloalkyl), - S02CH (RY) (C3-C7cycloalkyl), or - NR10SO2CH (RY) (C3-C7cycloalkyl), where RY is halogen or RY is d-C6alkyl, C2-C6alkanoyl, (C3-C7cycloalkyl) Co-C4alkyl, (C4-C7c-cycloalkenyl) Co-C4alkyl, (aryl) C0-C alkyl, (ar!) C0-C4alkoxy, (heterocycloalkyl) C0-C2alkyl, or (heteroaryl of 5 to 10 mers) C0-C alkyl, each of which is optionally substituted. River. R11 and R12 independently are at each occurrence hydrogen, or Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, (aryl) C0-C2alkyl, (C3-C7cycloalkyl) C0-C2alkyl, (C3-C7cycloalkenyl) C0-C2alkyl, (heterocycloalkyl) C0-C2alkyl, or C0-C2alkyl (5- to 10-membered heteroaryl), each of which is optionally substituted. Ri3 is hydrogen or Ci-C2alkyl. R11 and 15 independently are hydrogen, hydroxyl, or Ci- C2alkyl. n is 0, 1, or 2. M is hydrogen, halogen, Ci-C2alkyl hydroxy, or Ci- C2alkoxy. And it is absent, CR18R19, NR20, S, O, -O (C = O) (NR20) -. NH (C = O) (NR20) -, NH (S = O) (NR20) -, or -0 (C = 0) -; or And it is taken together with one of J, L, or M to form a ring. J is CH2 or J is taken together with Y to form a 3- to 7-membered carbocyclic or heterocyclic ring, which ring is substituted with 0 or 1 or more substituents independently selected from halogen, hydroxy, amino, cyano, C1-C2alkyl, C -C2alkoxy, Ci-C2alkoxy, trifluoromethyl, and trifluoromethoxy; when J it is taken together with Y to form a Z ring may be absent. L is CH2 or L is taken together with Y to form a 3- to 7-membered carbocyclic or heterocyclic ring, which ring is substituted with 0 or 1 or more substituents independently selected from halogen, hydroxy, amino, cyano, C-C2alkyl, C1 -C2alkoxy, C1-C2alkoxy, trifluoromethyl, and trifluoromethoxy; when L is taken together with Y to form a Z ring it may be absent. Z is (C0-C2alkyl) mono- or (mono- or bicyclic heteroaryl) Co-C2alkyl, each of which Z is substituted with 0 or 1 or more substituents independently selected from halogen, amino hydroxy, cyano, - CONH2, -COOH, -S02NR11R12, (C = 0) NR11R12, -NR (C = 0) R12, d-Cisalkyl, C2-C4alkanoyl, C4-C4alkoxy, C1-C4alkylthio, mono- and di-C1-C4alkylamino, Ci-C4alkylester, C1-C2haloalkyl, and C1-C2haloalkoxy, and 0 or 1 (C3-C7cycloalkyl) C0-C2alkyl, (phenyl) C0-C2alkyl, (phenyl) C0-C2alkoxy, (5- or 6-membered heteroaryl) C0- C2alkyl, (5- or 6-membered heteroaryl) C0-C2alkoxy, naphthyl, indanyl, (5- or 6-membered heterocycloalkyl) C0-C2alkyl, or 9- or 10-membered bicyclic heteroaryl, each of which is substituted with 0.1 , or 2 substituents independently selected from: (c) halogen, amino hydroxy, cyano, nitro, -COOH, -CONH2, CH3 (C = 0) NH-, = NOH, C1-C4alkyl, Ci-C4alkoxy, C1-C4hydroxyacyl > mono- and di-C1-C4alkylamino, -NR8S02R, -C (0) OR, -NR8COR, -NR8C (0) ORn, trifluoromethyl, and trifluoromethoxy, and (d) phenyl and heteroaryl of 5 or 6 members, each of the which is substituted with 0 or 1 or more halogen, Cr C4alkyl hydroxy, and dC2alkoxy. Ri 6 represents 0 to 4 substituents, is independently selected from halogen, d-dalkyl, and C-i-C2alkoxy. R1 and Rig independently are hydrogen, hydroxyl, halogen, d-dalkyl, C1-C2alkoxy, C1-C2haloalkyl, or Ci-C2haloalkoxy. R20 is hydrogen, C-i-C2alkyl, C1-C2haloalkyl, or Ci-C2haloalkoxy. Some compounds of Formula I described herein exhibit good activity in a replication analysis of HCV, such as the replicon of the HCV assay set forth in Example 3, below. Preferred compounds of Formula I have an EC50 of about 40 micromolar or less, or more preferably an EC50 of about 10 micromolar or less; or even more preferably an EC50 of about 5 nanomolar or less in a HCV replicon replication assay. DETAILED DESCRIPTION OF THE INVENTION Physical description and terminology Before discussing the invention in detail, it may be useful to provide definitions of some terms that will be used herein. The compounds of the present invention are described using standard nomenclature. Unless defined otherwise, all technical and scientific terms used here have the same meaning commonly understood by a person trained in the art to which this invention pertains. Unless clearly contraindicated by the context, each compound name includes the free acid or free base form of the compound, as well as hydrates of the compound and all pharmaceutically acceptable salts of the compound. The term "4-amino-4-oxobutanoyl peptides" encompasses all compounds satisfying formula I, including any enantiomers, racemates and stereoisomers, as well as all pharmaceutically acceptable salts of these compounds. The term "a compound of Formula I" includes all forms of these compounds, including salts and hydrates, unless clearly contraindicated by the context in which this expression is used. The terms "a" and "an" do not indicate a quantity limitation, but rather indicate the presence of at least one of the elements to which reference is made. The term "or" means "and / or". The terms "comprising", "having", "including", and "containing" should be interpreted as terms with open ends (ie, meaning "including, without limitation"). The enumeration of ranges of values is merely intended to serve as an abbreviated writing method to refer individually to each separate value that falls within the range, unless otherwise stated here or clearly contraindicated by the context. The use of each and every one of the examples, or the language of examples (eg, "such as"), is merely intended to better illustrate the invention and does not imply a limitation of the scope of the invention unless otherwise claimed. No language in the specification shall be construed as indicative of any unclaimed element as essential to the practice of the invention as used herein. Unless otherwise defined, the technical and scientific terms used herein have the same meaning as commonly understood by a person skilled in the art to which this invention pertains. An "active agent" means a compound (including a compound of the invention), element or mixture that when administered to a patient, alone or in combination with another compound, element or mixture, confers, directly or indirectly, a physiological effect in the patient. The indirect physiological effect can occur through a metabolite or other indirect mechanism. When the active agent is a compound, then salts, solvates (including hydrates) of the free compound, crystalline forms, non-crystalline forms and any polymorphs of the compound are included. The compounds may contain one or more asymmetric elements such as stereogenic centers, stereogenic axes and the like, for example, asymmetric carbon atoms, such that the compounds may exist in different stereoisomeric forms. These compounds, for example, can be racemates or optically active forms. For compounds with two or more asymmetric elements, these compounds can additionally be mixtures of diastereomers. For compounds that have asymmetric centers, all optical isomers in pure form and mixtures thereof are included. In addition, compounds with carbon-carbon double bonds can appear in Z- and E- forms, with all isomeric forms of the compounds. In these situations, simple enantiomers, that is, optically active forms, can be obtained by asymmetric synthesis, synthesis of pure optical precursors, or by resolution of the racemates. The resolution of the racemates can also be achieved, for example, by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, using, for example, a column for chiral HPLC. All the forms are contemplated here regardless of the methods used to obtain them. A hyphen ("-") is used that is not between two letters or symbols to indicate a point of attachment to a substituent. For example, the - (CH2) C3-C8C1cloalkyl is attached through the carbon of the methylene group (CH2). "Alkanoyl" denotes an alkyl group as defined herein, linked through a keto bridge (- (C = 0) -). The alkanoyl groups have the indicated amount of carbon atoms, with the carbon of the keto group included in the carbon atoms numbered. For example, a C2alkanoyl group is an acetyl group having the Formula CH3 (C = 0) -. A union represented by a combination of a solid dotted line, ie _ may be a single bond or double. "Alkyl" is a straight or branched chain saturated aliphatic hydrocarbon group, having the specified amount of carbon atoms, generally from 1 to about 12 carbon atoms. The term Ci-C6alkyl as used herein denotes an alkyl group having from 1 to about 6 carbon atoms. Other embodiments include alkyl groups having from 1 to 8 carbon atoms, 1 to 4 carbon atoms or from 1 to 2 carbon atoms, for example C-i-C8alkyl, C4alkyl, and C! -C ^ alkyl. When C0-Cnalkyl is used here in conjunction with another group, for example, (aryl) C0-C4alkyl, the indicated group, in this case aryl, is linked directly by a single covalent bond (C0), or linked by an alkyl chain having the specified amount of carbon atoms, in this case from 1 to about 4 carbon atoms. C0- Cnalkyl is used in conjunction with heteroaryl, aryl, phenyl, cycloalkyl, and heterocycloalkyl, for example, (heteroaryl of 5 to 10 mers) C0-C2alkyl, (aryl) C0-C2alkyl, (phenyl) C0-C2alkyl, (C3-C7cycloalkyl) C0-C4alkyl, and (C10-C4-heterocycloalkyl) alkyl. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, 3-methylbutyl, t-butyl, n-pentyl, and sec-pentyl. "Alkenyl" means a straight or branched hydrocarbon chain containing one or more unsaturated carbon-carbon double bonds, which may occur at any stable point throughout of the chain. The alkenyl groups described herein have the indicated amount of carbon atoms. For example C2-C6alkenyl denotes an alkenyl group from 2 to about 6 carbon atoms. When no number of carbon atoms are indicated, the alkenyl groups described herein commonly have from 2 to about 12 carbon atoms, although it is preferred to lower alkenyl groups, which have 8 or fewer carbon atoms. Examples of alkenyl groups include ethenyl, propenyl and butenyl groups. "Alkynyl" denotes a straight or branched hydrocarbon chain containing one or more triple carbon-carbon bonds, which may occur at any stable point along the chain. The alkenyl groups described herein have the indicated amount of carbon atoms. For example C2-C6alkynyl denotes an alkynyl group from 2 to about 6 carbon atoms. When no number of carbon atoms is indicated, the alkynyl groups described herein commonly have from 2 to about 12 carbon atoms, although lower alkynyl groups having 8 or less carbon atoms are preferred. "Alkoxy" means an alkyl group as defined above having the indicated amount of carbon atoms attached through an oxygen bridge (-O-). Examples of alkoxy include, if not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, 2-butoxy, t-butoxy, n-pentoxy, 2-pentoxy, 3-pentoxy, isopentoxy, neopentoxy, n-hexoxy, 2-hexoxy, 3-hexoxy, and 3-methylpentoxy. When "C0-nalcox" is used with another group, for example, (heteroaryl) C0-C4alkoxy, the indicated group, in this case heteroaryl, is linked by a covalently bonded oxygen bridge (C0alkoxy), or linked by an alkoxy group having the specified amount of carbon atoms, in this case from 1 to about 4 carbon atoms, which is covalently linked to the group it replaces by means of the oxygen atom of the alkoxy. The term "alkyl ester" denotes an alkyl group as defined herein linked through an ester linkage. The ester linkage can be in any orientation, for example a group of the formula -0 (C = 0) alkyl or a group of the formula - (C = 0) Oalkyl. "Alkylthio" means alkyl-S-, wherein the alkyl group is an alkyl group as defined herein having the indicated amount of carbon atoms and the point of attachment of the alkylthio substituent is on the sulfur atom. An exemplary alkylthio group is methylthio. "Aryl" indicates an aromatic group that only contains carbon in the ring or aromatic rings. These aromatic groups may be further substituted with carbon or non-carbon atoms or groups. Typical aryl groups contain 1 or 2 separate rings, fused or sloping and form from 6 to about 1 2 atoms in the ring, without heteroatoms as ring members. When indicated, the aryl groups may be substituted. This substitution may include fusion to a saturated cyclic group of 5-7 members containing optionally 1 or 2 heteroatoms independently selected from N, O, and S, to form, for example, a 3,4-methylenedioxy-phenyl group. Aryl groups include, for example, phenyl, naphthyl, including 1-naphthyl and 2-naphthyl, and bi-phenyl. In the term "(aryl) alkyl," aryl and alkyl are as defined above, and the point of attachment is in the alkyl group. "(Aryl) C0-C4alkyl" denotes an aryl group that is directly linked by means of a single covalent (aryl) C0alkyl bond or is linked through an alkyl group having from 1 to about 4 carbon atoms. Examples of (aryl) alkyl groups include piperonyl and (phenyl) alkyl groups such as benzyl and phenylethyl. Similarly, the term "(aryl) C0-C4alkoxy" denotes an aryl group which is directly linked to the molecule which it substitutes by means of an oxygen bridge, for example (aryl) C0alkoxy, or is covalently linked to a alkoxy group having from 1 to 4 carbon atoms. A "carbocyclic ring" is a saturated, partially unsaturated or aromatic cyclic group containing only carbon atoms in the ring. A "5- to 7-membered carbocyclic ring" has from 5 to 7 carbon atoms in the ring. Unless otherwise indicated, the carbocyclic ring may be attached to its pendant group at any carbon atom that results in a stable structure. When indicated, the carbocyclic rings described herein may be substituted at any carbon in the available ring if the resulting compound is stable.

Carbocyclic rings include cycloalkyl groups, such as cyclopropyl and cyclohexyl; cycloalkenyl groups, such as cyclohexenyl, bridged cycloalkyl groups; and aryl groups, such as phenyl. "Cycloalkyl" is a group with a saturated hydrocarbon ring, having the specified amount of carbon atoms. Monocyclic cycloalkyl groups commonly have from 3 to about 8 carbon atoms in the ring or from 3 to about 7 carbon atoms in the ring. The cycloalkyl substituents may be pendent of a carbon atom or substituted nitrogen, or a substituted carbon atom which may have two substituents may have a cycloalkyl group, which is attached as a spiro group. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl as well as bridged or caged saturated ring groups, such as norbornane or adamantane. Similarly, "cycloalkenyl" is a group with a hydrocarbon ring having the indicated amount of carbon atoms and at least double carbon-carbon between the ring carbon atoms. The terms "(cycloalkyl) C0-Cnalkyl" and "(cycloalkenyl) C0-C4alkyl" indicate a substituent in which the cycloalkyl or the cycloalkenyl and the alkyl are as defined herein, and the point of attachment of the group (cycloalkyl) alkyl or of the group (cycloalkenyl) alkyl to the molecule which it replaces is either a simple covalent bond, (C0alkyl) or in the alkyl group. (Cycloalkyl) alkyl embraces, not limited to, cyclopropylmethyl, cyclohexylmethyl, and cyclohexylmethyl. "Haloalkyl" denotes straight or branched chain alkyl groups having the specified amount of carbon atoms, substituted with 1 or more halogen atoms, up to the maximum available amount of halogen atoms. Examples of haloalkyl include, but are not limited to, trifiuoromethyl, difluoromethyl, 2-fluoroethyl, and penta-fluoroethyl. "Haloalkoxy" denotes a haloalkyl group as defined herein linked through an oxygen bridge (oxygen of a radical alcohol). "Halo" or "halogen" denotes any of fluoro, chloro, bromo and iodo. "Heteroaryl" denotes a stable monocyclic aromatic ring having the indicated amount of atoms in the ring containing from 1 to 3, or in some embodiments from 1 to 2, selected heteroatoms of N, O, and S, with carbon remaining ring atoms, or a stable bicyclic or tricyclic system containing at least one 5-7 membered aromatic ring containing from 1 to 3, or in some embodiments from 1 to 2, selected heteroatoms of N, O, and S, the remaining atoms of the ring being carbon. Monocyclic heteroaryl groups commonly have from 5 to 7 ring atoms. In some embodiments, the bicyclic heteroaryl groups are heteroaryl groups of 9 to 10 members, ie, groups containing 9 or 10 atoms in the ring, in which a 5-7 membered aromatic ring is fused to a second aromatic or non-aromatic ring. The "tricyclic heteroaryl" groups contain three fused rings, at least one of which is a heteroaryl ring. When the total amount of S and O atoms in the heteroaryl group exceeds 1, these heteroatoms are not adjacent to each other. It is preferred that the total amount of S and O atoms in the heteroaryl group is not more than 2. It is particularly preferred that the total amount of S and O atoms in the aromatic heterocycle is not more than 1. Examples of heteroaryl groups include, but are not limited to, oxazolyl, pyranyl, pyrazinyl, pyrazolopyrimidinyl, pyrazolyl, pyridizinyl, pyridyl, pyrimidinyl, pyrrolyl, quinolinyl, tetrazolyl, thiazolyl, thienylpyrazolyl, thiophenyl, triazolyl, benzo [d] oxazolyl, benzofuranyl, benzothiazolyl, benzothiophenyl, benzoxadiazolyl , dihydrobenzodioxinyl, furanyl, imidazolyl, indolyl and isoxazolyl. The term "heterocycloalkyl" denotes a saturated monocyclic group having the indicated number of atoms in the ring and containing from 1 to about 3 heteroatoms selected from N, O, and S, with the remaining carbon atoms in the ring being carbon, or saturated bicyclic ring system having at least one atom of N, O, or S in the ring, with the remaining carbon being carbon. Monocyclic heterocycloalkyl groups usually have from 4 to about 8 ring atoms. In some embodiments monocyclic heterocycloalkyl groups have from 5 to 7 ring atoms. The groups Bicyclic heterocycloalkyl commonly have from about five to about 1 2 ring atoms. Examples of heterocycloalkyl groups include morpholinyl, piperazinyl, piperidinyl and pyrrolidinyl groups. The term "(heterocycloalkyl) alkyl" denotes a saturated substituent in which heterocycloalkyl and alkyl are as defined herein, and the point of attachment of the group (heterocycloalkyl) alkyl to the molecule substituted by it is in the alkyl group. This term includes, but is not limited to, piperidylmethyl, piperazinylmethyl, and pyrrolidinylmethyl. The term "heterocyclic ring" denotes a saturated, partially unsaturated, or aromatic cyclic group having the indicated amount of ring atoms, commonly from 5 to 8 ring atoms, and containing from 1 to about 4 heteroatoms selected from N , O, and S, with carbon remaining ring atoms, or heterocyclic ring system or saturated, partially unsaturated or aromatic tricyclic, bicyclic, containing at least one heteroatom in the system selected from N multiple ring, or, and S and containing up to about 4 heteroatoms independently selected from N, O, and S in each ring of the multiple ring system. Bicyclic and tricyclic rings having the indicated number of ring atoms with heterocyclic ring systems commonly bicyclic having 7 to January 1st ring atoms and tricyclic systems with from 10 to 1 5 atoms in the ring. The group examples heterocyclics include, pyridyl, indolyl, pyrimidinyl, pyridyzinyl, pyrazinyl, imidazolyl, oxazolyl, furanyl, thiophenyl, thiazolyl, triazolyl, tetrazolyl, isoxazolyl, quinolinyl, pyrrolyl, pyrazolyl, benz [b] thiophenyl, isoquinolinyl, quinazolinyl, quinoxalinyl, thienyl, , isoindolyl, dihydroisoindolyl, 5,6,7,8-tetrahid roisoquinolina, pyridinyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, and pyrrolidinyl. Other examples of heterocyclic groups include, without limitation, 1, 1-dioxo-thieno-tetrahydrothiopyranyl, 1, 1 -dioxotiocromanilo, 1, 4-dioxanyl, 5-pteridinyl, tetrahydroindazolyl, azetidinyl, benzimidazolyl, benzisoxazinilo, benzodioxanyl, Benzodioxolyl, benzofurazanyl, benzoisoxolilo, benzopyranyl, benzopyrazolyl, benzotetrahydrofuranyl, benzotetrahidrotienilo, benzothiopyranyl, benzotriazolyl, benzoxazini it, benzoxazolinonyl, benzoxazolyl, beta-carbolinyl, carbazolyl, carbolinyl, chromanonyl, chromanyl, cinnolinyl, coumarinyl, dihydroazetidinyl, dihidrobenzisotiazinilo, dihidrobenzisoxazinilo, dihid robenzodioxinilo , dihydrobenzofuranyl, dihydrobenzoimidazolyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydrocoumarinyl, dihydroindolyl, dihidroisocumarinilo, dihydroisooxazolyl, dihidroisoquinolinonilo, dihydroisothiazolyl, dihydrooxadiazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihidropiririmidinilo, ropirrolilo dihid, dihidroquinolinonilo, di hidroquinolinilo, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, hexahydroazepinyl , imidazopyrazinyl, imidazopyridazinyl, Midazopyridinyl, midazopyridyl, midazopyrimidinyl, imidazothiadiazolyl, imidazothiazolyl, imidazothiophenyl, indolinyl, indolizinyl, isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, sobenzothienyl, isochromanyl, isocoumarinyl, isoindolinonyl, isoindolinyl, isoquinolyl, isothiazolyl, isoxazolyl, methylenedioxybenzyl. naphthyridinyl, oxadiazolyl, oxazolopyridinyl, oxazolyl, oxetanyl, oxopiperidinyl, oxopirazolilo, oxopyridinyl, fenotbiazi nile, phenoxazinyl, phthalazinyl, purinyl, pyrazinyl, pirazolopirazinilo, pyrazolopyridazinyl, pyrazolopyridyl, pirazolopi rimidinilo, pirazolotiofenilo, pirazolotriazinilo, pyridazinyl, pyridopyridinyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydrofuranyl, tetrahidroimidazopirazinilo, tetrahidroimidazopiridazinilo, tetrahidroimidazopiridinilo, tetrahidroimidazopirimidilo, tetrahidroisoquinolini it, tetrahydropyranyl, tetrahidropirazolopirazinilo, tetrahidropirazolopiridinilo, tetrahidropirazolopirimidi it, tetrahydroquinolinyl, idrotienilo Tetrah, tetrahidrotriazolopirimidilo, tetrahidrotriazolopirazinilo, tetrahidrotriazolopiridazinilo, tetrahidrotriazopiridinilo, tetrazolopyridyl, tetrazol'ilo, tiadiazoli it, thieno-tetrahidrotbiopiranilo, thienyl, thiochromanyl, triazinyl, thiazolopyrazinyl, triazolopyridazinyl, triazolop iridyl, triazolopyrimidinyl, triazoothiophenyl, and, when possible, N-oxides thereof. "Hydroxyalkyl" is an alkyl group having the indicated amount of carbon atoms and is substituted with at least one hydroxyl substituent. When indicated, the hydroxyalkyl group may be further substituted. The term "mono- and / or di-alkylamino" denotes secondary or tertiary alkylamino groups, wherein the alkyl groups independently are chosen alkyl groups, as defined herein, having the indicated amount of carbon atoms. The point of attachment of the alkylamino group is in the nitrogen. Examples of mono- and di-alkylamino groups include ethylamino, dimethylamino, and methyl-propylamino. "Mono- and / or di-alkylcarboxamide" denotes a mono-alkylcarboxamide group of the Formula (alkylol) -N H- (C = 0) - or a dialkylcarboxamide group of the formula (alkylol) (alkyl2) -N- (C = 0) - in which the point of attachment of the mono- or dialkylcarboxamide substituent to the molecule it replaces is in the carbon of the carbonyl group. The term "mono and / or dialkylcarboxamide" also includes groups of the formula (alkylol) (C = 0) NH- and (alkylol) (C = 0) (alkyl2) N- in which the point of attachment is the nitrogen. The alkylol and alkyl groups independently are selected alkyl groups having the indicated amount of carbon atoms. "Oxo," means a keto group (C = 0). An oxo group that is a substituent of a non-aromatic carbon atom results in a conversion of -CH2- to -C (= 0) -. An oxo group that is a substituent of an aromatic carbon atom results in a conversion of -CH- to -C (= 0) - and a loss of aromaticity.

The term "substituted", as used herein, means that one or more of any of the hydrogens in the designated atom or group is replaced with a selection of the indicated group, provided that the normal valence of the designated atom is not exceeded. When the substituent is oxo (ie, = 0) then 2 hydrogens on the atom are replaced. When an oxo group substitutes aromatic portions, the corresponding partially unsaturated ring replaces the aromatic ring. For example, a pyridyl group substituted by oxo is a pyridone. Substitutant and / or variable combinations are permissible only if these combinations produce stable compounds or useful synthetic intermediates. A stable compound or a stable structure means that it involves a compound that is sufficiently robust to survive the isolation of a reaction mixture, and to the subsequent formulation into an effective therapeutic agent. Unless otherwise specified, the substituents are named in the main structure. For example, it will be understood that when (cycloalkyl) alkyl is indicated as a possible substituent, the point of attachment of this substituent to the backbone is in the alkyl portion. Suitable groups that may be present in a "substituted" position include, but are not limited to, for example, halogen; cyano; hydroxyl; nitro; azido; alkanoyl (such as a C2-C6 group such as acyl or the like); carboxamido; alkyl groups (including cycloalkyl groups, which have from 1 up to about 8 carbon atoms, or from 1 to about 6 carbon atoms); alkenyl and alkynyl groups (including groups having one or more unsaturated bonds and from 2 to about 8, or from 2 to about 6 carbon atoms); alkoxy groups having one or more oxygen bonds and from 1 to about 8, or from 1 to about 6 carbon atoms; aryloxy such as phenoxy; alkylthio groups including those having one or more thioether bonds and from 1 to about 8 carbon atoms; or from 1 to about 6 carbon atoms; alkylsulfonyl groups including those having one or more sulphonyl bonds and from 1 to about 8 carbon atoms, or from 1 to about 6 carbon atoms; alkylsulfonyl groups including those having one or more sulfonyl bonds and from 1 to about 8 carbon atoms, or from 1 to about 6 carbon atoms; aminoalkyl groups, including groups having one or more N atoms and from 1 to about 8, or from 1 to about 6 carbon atoms; aryl having 6 or more carbons and one or more rings, (for example, phenyl, biphenyl, naphthyl, or the like, each substituted or unsubstituted aromatic ring); arylalkyl having from 1 to 3 separate or fused rings and from 6 to about 18 carbon atoms in the ring, the benzyl being an exemplary arylalkyl group; Arylalkoxy having from 1 to 3 separate or fused rings and from 6 to about 18 carbon atoms in the ring, with benzyloxy being an exemplary arylalkoxy group; or a saturated, unsaturated or aromatic heterocyclic group having from 1 to 3 separate or fused rings with 3 to about 8 members per ring and one or more N, O or S atoms, for example coumarin, quinolinyl, isoquinolinyl, quinazolinyl, pyridyl , pyrazinyl, pyrimidinyl, furanyl, pyrrolyl, thienyl, thiazolyl, triazinyl, oxazolyl, isoxazolyl, imidazolyl, indolyl, benzofuranyl, benzothiazolyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, mofolinyl, piperazinyl, and pyrrolidinyl. These heterocyclic groups may be further substituted, for example with hydroxy, alkyl, alkoxy, halogen and amino. A "vinyl" group is a substituent of the formula -HC ===. A "dosage form" means a unit of administration of an active agent. Examples of dosage forms include tablets, capsules, injections, suspensions, liquids, emulsions, creams, ointments, suppositories, inhalable forms, transdermal forms, and the like. "Pharmaceutical compositions" are compositions containing at least one active agent, such as a compound or salt of Formula I, and at least one other substance, such as a carrier, excipient or diluent. The pharmaceutical compositions comply with the GMP (good manufacturing practices) standards of the United States FDA for drugs for humans or non-humans. "Pharmaceutically acceptable salts" includes derivatives of the described compounds, in which the parent compound is modified by making inorganic and organic, non-toxic salts thereof, acid or base addition salts. The salts of the present compounds can be synthesized from an originating compound that contains an acidic or basic portion by conventional chemical methods. Generally, these salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, or the like), or by reacting forms of free base of these compounds with a stoichiometric amount of the appropriate acid. These reactions are commonly carried out in water or in an organic solvent, or in a mixture of the two. Non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile, when applicable, are generally preferred. Salts of the present compounds also include solvates of the compounds and salts of the compounds. Examples of pharmaceutically acceptable salts include, but are not limited to, salts of organic or mineral acid from basic residues such as amines; alkaline or organic salts of acidic residues, such as carboxylic acids; and similar. The pharmaceutically acceptable salts include the conventional non-toxic salts and the quaternary ammonium salts of the parent compound formed, for example, from non-toxic organic or inorganic acids. For example, conventional salts of non-toxic acids include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitrite and the like; and salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, melic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymethyl, phenylacetic, glutamic, benzoic, salicylic, mesylic, silyl, besylic , sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, HOOC- (CH2) n -COOH wherein n is 0-4, and the like. Additional lists of appropriate salts can be found, for example, in Remington's Pharmaceutical Sciences, 1 7a. ed. , Mack Publishing Company, Easton, Pa., P. 1 41 8 (1985). The term "carrier" applied to pharmaceutical compositions of the invention refers to a diluent, excipient, or vehicle with which an active compound is provided. A "pharmaceutically acceptable excipient" means an excipient that is useful in the preparation of a pharmaceutical composition that is generally safe, non-toxic and is not biologically or otherwise undesirable, and includes an excipient that is acceptable for veterinary use, as well as for pharmaceutical use in humans. A "pharmaceutically acceptable excipient" as used in the present application includes both one and more than one of these excipients. A "patient" is a human or non-human animal that needs medical treatment. Medical treatment may include treatment of an existing condition, such as a disease or disorder, prophylactic or preventive treatment, or diagnostic treatment. In some modalities the patient is a human patient. "Prodrug" means any compound that becomes the compound of the invention when administered to a mammalian subject, for example, upon metabolic processing of the prodrug. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate and similar derivatives of functional groups (such as alcohol or amine groups) in the compounds of the invention. "Providing" means giving, administering, selling, distributing, transferring (whether for consideration or not), manufacturing, composing or dispensing. "Providing a compound of Formula I with at least one additional active agent" means that the compound of Formula I and the additional active agent or agents are provided simultaneously in a single dose form, are provided in separate dosage forms for administration separated by some amount of time that is within the time in which both the compound of Formula I and the at least one additional active agent are within the bloodstream of a patient. The compound of Formula I and the additional active agent do not have to be prescribed for a patient by the same physician. The additional active agent or agents do not have to have a prescription. The administration of the compound of Formula I or the at least one Additional active agent can occur by any appropriate route for example, oral tablets, oral capsules, oral fluids, inhalation, injection, suppositories or topical contact. "Treatment" as used herein includes providing a compound of Formula I and at least one additional active agent sufficient to: (a) prevent a disease or a symptom of a disease from occurring in a patient who may be predisposed to the disease but who has not yet been diagnosed as having it (for example, including diseases that may be associated with or that may be caused by a primary disease (such as in liver fibrosis, which may be the result in the context of chronic infection). HCV), (b) inhibiting the disease, ie stopping its development, and (c) relieving the disease, that is, causing regression of the disease. "Treating" and "treating" also mean providing a therapeutically effective amount of a compound of the Formula I and at least one additional active agent to a patient having or being susceptible to a Hepatitis C infection. A "therapeutically effective amount" of a The pharmaceutical composition of this invention means an effective amount, when administered to a patient, to provide a therapeutic benefit, such as an improvement in symptoms, for example, an effective amount to decrease the symptoms of a Hepatitis C infection. For example a patient infected with a hepatitis virus. C may present elevated levels of some enzymes, including AST and ALT. Normal levels of AST are from 5 to 40 units per liter of serum (the liquid part of the blood) and normal levels of ALT are from 7 to 56 units per liter of serum. A therapeutically effective amount is therefore an amount sufficient to provide a significant reduction in elevated levels of AST and ALT or an amount sufficient to provide a return of AST and ALT levels to the normal range. A therapeutically effective amount is also an amount sufficient to prevent a significant increase or significantly reduce the detectable level of virus or viral antibodies in the blood, serum or tissues of the patient. One method for determining treatment efficacy includes measuring HCV RNA levels by a conventional method to determine viral RNA levels such as Taq an Roch analysis. In some preferred embodiments, treatment reduces levels of HCV RNA below the limit of quantification (30 IU / mL, as measured by the TaqMan (R) Roche assay) or more preferably below the detection limit (10 IU / mL). , TaqMan Roche). A significant increase or decrease in the detectable level of viruses or viral antibodies is any detectable change that is statistically significant in a standard parametric test of statistical significance, such as the Student's t-test, where p < 0.05. Chemical description Formula I includes all the sub-formulas of it. In some situations, the compounds of Formula I may contain one or more asymmetric elements such as stereogenic centers, stereogenic axes and the like, for example asymmetric carbon atoms, such that the compounds may exist in different stereoisomeric forms. These compounds, for example, can be racemates or optically active forms. For compounds with two or more asymmetric elements, these compounds can additionally be mixtures of diastereomers. For compounds having asymmetric centers, it will be understood that all optical isomers and mixtures thereof are included. In addition, compounds with carbon-carbon double bonds can appear in their Z- and E- forms, with all the isomeric forms of the compounds included in the present invention. In these situations, the single enantiomers, that is, optically active forms, can be obtained by asymmetric synthesis, synthesis from optically pure precursors, or by resolution of the racemates. The resolution of the racemates can also be carried out, for example, by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, using, for example, a column for chiral HPLC.

When there is a compound in various tautomeric forms, the invention is not limited to any of the specific tautomers, instead it includes all tautomeric forms. The present invention is intended to include all isotopes of atoms that occur in the compounds herein. The Isotopes include those atoms that have the same atomic number but different mass numbers. By way of general example, and without limitation, the isotopes of hydrogen include tritium and deuterium, and the carbon isotopes include 11C, 13C, and 14C. Some compounds are described herein using a general formula including variables, for example R1-R9, Ri6, Rie. Ri9. n, M, Y, and Z. Unless otherwise specified, each variable within this type of Formula is defined independently of other variables. Thus, if a group is said to be substituted, for example with 0-2 R *. then the group can be substituted with up to two groups R * and R * in each case is selected independently of the definition of R *. Also, combinations of substituents and / or variables are permissible only if these combinations result in stable compounds. In addition to the compounds of Formula I as described above, the invention also includes compounds of Formula I in which one or more of the following conditions are met for the variables R1-R9, Ri6, Rie. R19. n, M, Y, and Z. The invention includes compounds of Formula I which carry any combination of the variable definitions set out below, which produce a stable compound.

(Formula I) In some modalities the variables R and R2 carry one of the definitions discussed below. (1) (2) Ri and R2 are joined to form a 5- to 7-membered heterocycloalkyl ring containing 1 or 2 heteroatoms independently selected from N, O, and whose ring is optionally fused to a 5- or 6-membered heteroaryl group ( for example phenyl or pyridyl) to form a bicyclic ring system, each of which 5- to 7-membered heterocycloalkyl rings is optionally substituted. (2) Ri and R2 are attached to form a pyrrolidine, piperidine or piperazine ring or to form a piperazine ring fused with a phenyl, each of which is optionally substituted with 0 to 3 substituents independently selected from A- and AB- in where A is halogen, amino hydroxy, cyano, -CONH2, -COOH, Ci-C4alkyl, C2-C4alkanoyl, C1-C alkoxy, Ci-C alkylthio, mono- or di- C1-C4alkylamino, C-C4alkylester, CrC4alkylsteramine, mono- or di-Ci-C4-alkylcarboxamide, or Ci- C2-haloalkoxy; and B is d-C4alkyl. (2) R1 and R2 are attached to form a pyrrolidine, piperidine or piperazine ring or a piperazine ring fused with a phenyl, each of which is optionally substituted with 0 to 2 substituents independently selected from halogen, amino hydroxyl, CONH2, - COOH, Ci-C2alkyl, and Ci-C2alkoxy. (3) Ri is C1-C40 (C = 0) -, CT-C ^ C ^) - (4) R2 is CT-Cealkyl or C3-C7c-chloroalkyl. (5) R2 is hydrogen. The variables R¾ to R «In some modalities the variables R3 to R8 carry one of the definitions discussed below. (1) R3) R4, R5, R6, R7, and e independently are (a) hydrogen, or (b) C1-C4alkyl or (C3-C7cycloalkyl) C0-C alkyl, each of which is substituted with 0 to 3 substituents independently selected from halogen, amino hydroxy, cyano, -CONH2, -COOH, C1-C4alkyl, C2-C4alkanoyl, Ci-C4alkoxy, C 1 -C 4alkyl, mono- and di-d-dalkylamino, C 1 -C 2 haloalkyl, and C 2 -C 2 haloalkoxy. (2) R3, R4, R5, R6, R7I and R8 independently are hydrogen, C-C4alkyl, or (C3-C7cycloalkyl) C0-C4alkyl. (3) R3, R4, R5) Re, R7, and R8 independently are hydrogen or methyl. (4) Any of R3 and R4 and / or R5 and R6, and / or R7 and R8 are joined to form a 3 to 7 membered cycloalkyl ring or 3-7 membered heterocycloalkyl ring containing 1 or 2 heteroatoms independently selected from N, S, and O, each of which rings, is substituted with 0 to 2 substituents independently selected from halogen, hydroxyl amino, cyano, vinyl, C1-C2alkyl, Ci-C2alkoxy, trifluoromethyl, and trifluoromethoxy. (5) Any of R3 and R and / or R5 and R6, and / or R7 and R8 are joined to form a 3- to 7-membered cycloalkyl ring or a 5- to 6-membered heterocycloalkyl ring containing 1 or 2 independently selected heteroatoms of N, S, and O, each of said rings is substituted with 0 to 2 substituents independently selected from halogen, Ci-C2alkyl hydroxyl, and d-dalkoxy. (6) R3, R4, and R6, independently are hydrogen or methyl; R5 is d-Cealkyl, C2-C6alkenyl, (C3-C7cycloalkyl) C0-C alkyl, (C3-C7cycloalkenyl) C0-C4alkyl, (heterocycloalkyl) C0-Calkyl, C2-C6alkanoyl, or mono- or di-d-Cealkylamino; Y R7 and Re are linked to form an optionally substituted 3 to 7-membered cycloalkyl ring or an optionally substituted 3 to 7 membered heterocycloalkyl ring containing 1 or 2 heteroatoms independently selected from N, S, and O. (7) R5 is C ^ Cealkyl or (C3-C7cycloalkyl) C0-C4alkyl; and R7 and R8 are joined to form a cyclopropyl ring, which is unsubstituted or is substituted with 1 or 2 Ci-C6alkyl or Ci-C6alkenyl. (8) The invention includes compounds in which R3 and R4 are hydrogen, R5 is hydrogen, R6 is t-butyl, and R7 and R8 are linked to form a cyclopropyl group substituted by a vinyl group. For example, the invention includes com ponents of Formula I I (Formula II) (9) R3, R4, R6) and R8 independently are hydrogen or methyl; and R8 is a saturated or unsaturated hydrocarbon chain of 7 to 11 carbon atoms that is covalently linked to R7, wherein R7 is a methylene group. For example the invention includes the compound of Formula I I I z (Formula wherein D is an alkyl or alkenyl group having 6 to 10 carbon atoms. (10) The invention also includes compounds in which R3 and R4 are both hydrogen, and R5 is covalently linked to R7 by an 8-membered monounsaturated hydrocarbon chain. For example, the invention includes compounds of Formula (IV) Formula IV). (11) R3, R4, and R6 independently are hydrogen or methyl; and R 5 is a saturated or unsaturated hydrocarbon chain of 7 to 1 1 carbon atoms that is covalently attached to an optionally substituted cycloalkyl ring, formed by R 7 and R 8 which are bonded to form an optionally substituted 3 to 7 membered cycloalkyl ring. For example the invention includes compounds and salts of Formula V (FormulaV) wherein D is an alkyl or alkenyl group having 6 to 10 carbon atoms. (1 2) The invention also includes compounds and salts in which R3 and R4 are both hydrogen and R5 is a monounsaturated hydrocarbon chain of 7 carbon atoms which is covalently linked to a substituted cycloalkyl ring formed by R7 and R8. For example the invention includes compounds and salts of Formula VI and VI-A: (Formula VI).

In some modalities, the variable R9 carries one of the definitions discussed below. (1) T is a group of the formula 10Rn, -OR12, - (C = O) OR10, or -CONR10Rn- (2) R9 is hydroxyl, amino, -COOH, -NRi0R, -OR12, -NR! Or SOsR, - (C = O) OR10, or -CONRujRn. (3) R9 is C! -Cealkyl, C2-C6alkenyl, C2-C6alkanoyl, (C3-C7cycloalkyl) C0-C4alkyl, (C3-C7cycloalkenyl) Co-C4alkyl, (C 1 -C 4 heteroaryloalkyl), C 0 -C 2 alkyl, (heteroaryl 5- to 10-membered) C 0 -C 2 alkyl, each of which is substituted with 0 or 1 or more substituents independently selected from halogen, hydroxyl amino, cyano , oxo -COOH, -CONH2, oxo, C4alkyl, C2-C4alkanoyl, Ci-C4alkylthio, mono- and di-C4C4alkylamino, C-C4alkyl ester, mono- and di- Ci-C4alkylcarboxamide, C1-C2haloalkyl, and Ci-C2haloalkoxy . (4) R9 is C! -Cealkyl, C2-C6alkenyl, C2-C6alkanoyl, (C3-C7cycloalkyl) C0-C4alkyl, (C3-C7cycloalkenyl) C0-C4alkyl, (heterocycloalkyl) C0-C4alkyl, (aryl) C0-C2alkyl, or (5- to 10-membered heteroaryl) C0-C2alkyl, each of which is substituted with 0 or 1 or more substituents independently selected from halogen, hydroxyl amino, cyano, oxo -COOH, -CONH2, Ci-C alkyl, C1 -C alkoxy, mono- and di-Ct-C alkylamino, C 1 -C 2 haloalkyl, and C 2 -C 2 haloalkoxy. (5) R9 is a phosphonate of the formula wherein p is 1 or 2 'and R13-R15 carry the values set forth in the section "Brief description of the invention". (6) R9 is RxXCi-C4alkyl-, wherein X is - (C = 0) NH-, -NH (C = 0) - and Rx is phenyl or pyridyl. (7) R9 is -CH (RY) (C3-C7cycloalkyl), -S02CH (RY) (C3-C7cycloalkyl), or -NR10SO2CI-l (RY) (C3-C7cycloalkyl), wherein RY is halogen, or RY is C2-C6alkanoyl, (C3-C7cycloalkyl) Co-C2alkyl, (phenyl) C0-C4alkyl, (phenyl) C0-C4alkoxy, (heterocycloalkyl) C0-C2alkyl, or (5-10 membered heteroaryl) C0-C4alkyl, each of which is substituted with 0 or 1 or more substituents independently selected from halogen; hydroxyl, amino, cyano, oxo -COOH, -CONH2, oxo, C1-C alkyl, Ci-C alkoxy, mono- and di-Ci-C4alkylamino, C-C2haloalkyl, and C -C2haloalkoxy. (8) R9 is -NR10SO2R. In some embodiments R 0 is hydrogen or methyl and R n is cyclopropyl. The variables Rm. Rn and Ri? In any of the above definitions of R9 the variables R-io, R, and R12 may carry the definition set forth for Formula I in the section "Brief description of the invention". R10, Rn, and Ri2 can also carry any of the definitions that follow (1) R10, R11, and R12 independently are d-Cealkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C7cycloalkyl) C0-Calkyl, (heterocycloalkyl) C0-C4alkyl :, (phenyl) C0-C2alkyl, (naphthyl) C0-C2alkyl, or (C10-C2alkyl (5- to 10-membered heteroaryl) alkyl, each of which is substituted with 0 to 3 substituents independently selected from halogen, hydroxyl amino, cyano, oxo -COOH, -CONH2) oxo , C1-C alkyl, C1-C4alkoxy, C2-C4alkanoyl, Ci-C4alkylthio, mono- and di-C1-C4alkylamino, Ci-C4alkylester, mono- and di- Ci-C4alkylcarboxamide, Ci-C2haloalkyl and Ci-C2haloalkoxy. (2) R 0, -11, and 12 independently are hydrogen, or Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C7cycloalkyl) C0-C2alkyl, (heterocycloalkyl) C0-C2alkyl, (phenyl) C0-C2alkyl or (5- to 6-membered monocyclic heteroaryl) C0-C2alkyl, each of which is substituted with 0 to 3 substituents independently selected from halogen, hydroxyl oxo, C ^ - ^ alkyl, Cr C2alkoxy, trifluoromethyl, and trifluoromethoxy . (3) R 0, Rii, and i2 independently are hydrogen or Cr C6alkyl. The variables Y. M. J. L. v Z The invention includes compounds and salts of Formulas I through VI in which Y, M, and Z carry the variables set forth below. Y, M, and Z include the variables n, Ri8 and Ri9- (1) Y is absent, is CH2, O, or -0 (C = 0) - and n is 0. (2) Y is O and n is 0. (3) And it is absent, it is CH2, O, or -0 (C = 0) -, and R1 8 and R1 9 independently are hydrogen or methyl, and n is 1. (4) The invention includes compounds and salts in which n is 1 . (5) M is hydrogen. (6) J and L are both CH2. (7) Z is 1-naphthyl, 2-naphthyl, (8) Z is a group of the formula Within the above chemical formula X1-X5, G1-G4, and R21-24 carry the following definitions. ?? X2, X3, X4 and X5 independently are N or CH and not more than Gi, G2, G3, and G4 independently are CH2, O, S, or NR24, where no more than two of Gi up to G4 are other than hydrogen. R21 represents from 0 to 3 groups independently selected from halogen, amino hydroxy, cyano, -CONH2, -COOH, C1-C4alkyl, C2-C4alkanoyl, C1-C4alkoxy, C1-C4alkylthio, mono- and di-C1-C4alkylamino, Ci- C2haloalkyl, and Ci-C2haloalkoxy. R22 is hydrogen, halogen, amino hydroxy, cyano, -CONH2I -COOH, C-C4alkyl, C2-C4alkanoyl, Ci-C4alkoxy, C1-C4alkylthio, mono- and di-C-C4alkylamino, Ci-C4alkylester, Ci-C2haloalkyl, and ?? -? S? ß ?? ß ?????, or R22 is (C3-C7cycloalkyl) C0-C2alkyl, (phenyl) C0-C2alkyl, (phenyl) C0-C2alkoxy, (5- or 6-membered heteroaryl) C0-C2alkyl, (5- or 6-membered heteroaryl) C0-C2alkoxy, naphthyl, indanyl, (5- or 6-membered heterocycloalkyl) C0-C2alkyl, or 0- or 10-membered bicyclic heteroaryl, each of which is substituted with 0, 1, or 2 substituents independently selected from (c) halogen, amino hydroxy, cyano, nitro, -COOH, -CONH2, CH3 (C = 0) NH-, dC ^ alkyl, Ci-C4alkoxy, C1-C4 hydroxyalkyl, mono- and di-C1-C4alkylamino, -NR8S02R, -C (0) OR, -NR8COR, -NR8C (0) OR, trifluoromethyl, trifluoromethoxy, and (d) phenyl and heteroaryl of 5 or 6 members, each of which is substituted with 0 or 1 or more of halogen, hydroxyl, d-C4alkyl, Ci-C2alkoxy. R23 is 0 to 2 substituents independently selected from halogen, C1-C2alkyl hydroxyl, and C1-C2alkoxy. R24 is independently selected at each occurrence between hydrogen and C1-C2alkyl. In some modalities R22 is Within this modality, X1-X5 and R21-R23 carry the following definitions. X1t X2, X3, and X4, independently are N or CH and not more than R21 represents from 0 to 3 groups independently selected from halogen, amino hydroxy, cyano, -CONH2, -COOH, C1-C4alkyl, -C2-C4alkanoyl, C1-Calkoxy, Ci-C4alkylthio, mono- and di-Ci-C4alkylamino , C ^ C ^ alkalyl, and C -C2haloalkoxy. R22 is hydrogen, halogen, amino hydroxy, cyano, -CONH2, -COOH, Ci-C4alkyl, C2-C4alkanoyl, C1-C4alkoxy, Ci-C4alkylthio, mono- and di-C1-C4alkylamino, C1-C4alkylester, Ci-C2haloalkyl, and Ci-C2haloalkoxy. O, R22 is (C3-C7cycloalkyl) CoC2alkyl, (phenyl) C0-C2alkyl, (phenyl) C0-C2alkoxy, (5- or 6-membered heteroaryl) C0-C2alkyl, (5- or 6-membered heteroaryl) C0-C2alkoxy, naphthyl, indanyl, (5- or 6-membered heterocycloalkyl) C0-C2alkyl, or bicyclic heteroaryl of 0 or 10 members, each of which is substituted with 0, 1, or 2 substituents independently selected from (c) halogen, amino hydroxy, cyano, nitro, -COOH, -CONH2, CH3 (C = 0) NH- , C1-C4alkyl, C1-C4alkoxy, C1-C4hydroxyalkyl, mono- and di-d-Cyalkylamino, -NR8S02Rn, -C (0) OR, -NR8CORn, -NR8C (0) OR, trifluoromethyl, and trifluoromethoxy, and (d) ) phenyl and heteroaryl of 5 or 6 members, each of which is substituted with 0 or 1 or more of halogen, Ci-C alkyl hydroxy, C-C2 alkoxy. (10) Z is a group of the formula where XrX5 and R2i-R22 carry the definitions set forth for mode (7), immediately preceding. (9) Z is a quinoline of the formula wherein X1-X5 and R2i-R22 carry the definitions set forth for mode (7). Or in some embodiments, R21 represents a substituent in position 7 of the quinoline, and 0 to 2 additional substituents independently selected from halogen, amino hydroxy, cyano, -CONH2, -COOH, Ci-C4alkyl, C2-C4alkanoyl, d ^ alkoxy, mono- and di-C1-C4alkylamino, Ci-C2haloalkyl, and Ci-C2haloalkoxy; and R22 is (C02) C0-C2alkyl or C0-C2alkyl (pyridyl) alkyl, each of which is substituted with 0, 1, or 2 substituents independently selected from halogen, hydroxyl amino, cyano, -COOH, -CONH2, C1- C4alkyl, Ci-C4alkoxy, mono- and di-Ci-C4alkylamino, trifluoromethyl, and trifluoromethoxy. (10) The invention includes compounds and salts wherein n is 0, Z is absent, and Y and M are taken together to form a ring, such that ru or ara the formula Within this mode d, G2, G3, G4, and G5 independently are CH2, O, S, or NR22; where no more than two of Gi, G2l G3, G4, and G5 are different from CH2. R21 is 0 to 2 independently selected substituents of halogen, hydroxy, Ci-C2alkyl, and C-C2alkoxy; R22 is independently selected at each occurrence between hydrogen and methyl; and R23 is 0 to 2 substituents independently selected from halogen, hydroxy, C-iC2alkyl, and dC2alkoxy. (1 1) The invention includes compounds and salts in which n is 0, M is hydrogen, Z is absent, and Y and J are taken together to form a ring, such that it's a group for the formula: Within this mode G,, G2, G3 and G4 independently are CH2, O, S, or NR22; where no more than two of G,, G2, G3 and G4 are different from CH2. R21 is 0 to 2 independently selected substituents of halogen, hydroxy, dC2alkyl, and Ci- C2alkoxy; R22 is 0 to 2 substituents independently selected from halogen, hydroxy, Ci- C2alkyl, and dC2alkoxy; and R23 is 0 to 2 substituents independently selected from halogen, hydroxy, dC2alkyl, and dC2alkoxy. (12) The invention also includes compounds and salts thereof, wherein it's a group for the formula: (13) The invention includes compounds where n is 0, Z is absent, and Y and L are taken together to form a ring, such that it's a group for the formula: Within this mode G1 f G2, G3, and G4 independently are CH2, O, S, or NR22; where no more than two of G ,, G2, G3, and G4 are other than CH2. Qi and Q2 independently are CH or N. R21 is 0 to 2 substituents independently selected from halogen, hydroxy, C1-C2alkyl, and CrC2alkoxy; R22 is 0 to 2 substituents independently selected from halogen, hydroxy, C, -C2alkyl, and C2C2alkoxy; and R23 is 0 to 2 substituents independently selected from halogen, hydroxy, CrC2alkyl, and Ci- C2alkoxy. (14) The invention includes compounds and salts wherein it's a group for the formula: The invention includes compounds and salts of Formula VII and Formula VIII in which Y is oxygen.

Formula VII Formula VIII Within this embodiment: Ri and R2 are linked to form a pyrrolidine, piperidine or piperazine ring or a piperazine ring fused with a phenyl, each of which is optionally substituted with 0 to 2 substituents independently selected from halogen, hydroxyl, amino, CONH2, -COOH, d-C2alkyl, and C1-C2alkoxy. R3, R4, R6, and Re independently are selected from hydrogen, C1-C4alkyl, and (C3-C7cycloalkyl) Co-C2alkyl. R9 is hydroxyl, amino, -COOH, -NR10R, -OR12, -NR10SO2Rii, - (C = O) OR10, or -CONR10Rn. R - ??, R11 and R12 independently are hydrogen, or C -C6alkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C7cycloalkyl) C0-C2alkyl, (heterocycloalkyl) C0-C2alkyl, (phenyl) C0-C2alkyl, or ( 5 to 6 membered monocyclic heteroaryl) C0-C2alkyl, each of which is substituted with 0 to 3 substituents independently selected from halogen, hydroxyl oxo, C1-C2alkyl, C - \ - C2alkoxy, trifluoromethyl, and trifluoromethoxy. R-, 6 is 0 to 2 substituents independently selected from halogen, C-i-C2alkyl, and 'Ci-C2alkoxy. M is hydrogen or methyl. (11) Z is a quinoline of the formula in a cua, R2i represents a substituent at position 7 of the quinoline, and 0 to 2 additional substituents independently selected from halogen, hydroxyl, amino, cyano, -CONH2, -COOH, Ci-C4alkyl, C2-C4alkanoyl, C1-C4alkoxy , mono- and di-Ci-C alkylamino, C 2 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy; and R22 is (C02) C0-C2alkyl or C0-C2alkyl (pyridyl) alkyl, each of which is substituted with 0, 1, or 2. substituents independently selected from halogen, hydroxyl amino, cyano, -COOH, -CONH2, C1 -C4alkyl, C1-C4alkoxy, mono- and di-d-Calkylamino, trifluoromethyl, and trifluoromethoxy. Pharmaceutical preparations The compounds of the invention can be administered as the pure chemical substance, but are preferably administered as a pharmaceutical composition. Accordingly, the invention provides pharmaceutical formulations containing a compound or pharmaceutically acceptable salt of the invention, together with at least one pharmaceutically acceptable carrier. The compounds of the invention can be administered orally, topically, parenterally, by inhalation or spray, sublingually, transdermally, by buccal, rectal administration, as an ophthalmic solution, or by other means, in dosage unit formulations that contain conventional pharmaceutically acceptable carriers. The pharmaceutical composition can be formulated as any pharmaceutically useful form, for example, as an aerosol, a cream, a gel, a pill, a capsule, a tablet, a syrup, a transdermal patch, or an ophthalmic solution. Some dosage forms, such as tablets and capsules, are subdivided into appropriately sized dose units containing appropriate amounts of the active components, for example, an effective amount to achieve the intended purpose. The carriers include excipients and diluents and must be of sufficiently high purity and of sufficiently low toxicity to make them suitable for administration to the patient being treated. The carrier can be inert or can provide pharmaceutical benefits by itself. The amount of carrier used in conjunction with the compound is sufficient to provide a practical amount of material for administration per unit dose of the compound. The classes of carriers include, but are not limited to, binders, buffering agents, coloring agents, diluents, disintegrants, emulsifiers, flavorings, glidants, lubricants, preservatives, stabilizers, surfactants, tabletting agents, and wetting agents. Some carriers may be listed in more than one class, for example vegetable oil can be used as a lubricant in some formulations and as a diluent in others. Examples of pharmaceutically acceptable carriers include sugars, starches, celluloses, powdered tragacanth, malt, gelatin; talcum, and vegetable oils. Optional active agents may be included in a pharmaceutical composition, which do not substantially interfere with the activity of the compound of the present invention. The binders are substances that bind or "stick" the powders and make them cohesive forming granules, thus serving as the "adhesive" in the formulation. Binders add cohesive strength to what is already available in the diluent or filler. Examples of agonists include starch, gelatin, natural sugars, corn sweeteners, natural and synthetic gums such as acacia, sodium alginate, carboxymethylcellulose, polyethylene glycol and waxes. The amount of binder in the composition may vary, for example, from about 2 to about 20% by weight of the composition, or from about 3 to about 10% by weight, even more preferably from about 3 to about 6% by weight. The diluents include sugars such as lactose, sucrose, mannitol and sorbitol; starches from wheat, corn, rice and potatoes; and celluloses such as microcrystalline cellulose. The amount of diluent in the composition can be, for example, from about 10 to about 90% by weight of the total composition, from about 25 to about 75%, from about 30 to about 60% by weight, or from about 1. 2 up to about 60%. The disintegrants are materials added to a pharmaceutical composition to help separate (disintegrate) and release the active agent. Suitable disintegrants include starches; including modified "cold water soluble" starches, such as sodium carboxymethyl starch; natural and synthetic gums such as locust bean, karaya, guar, and gum tragacanth and agar; cellulose derivatives such as methylcellulose and sodium carboxymethylcellulose; microcrystalline celluloses and cross-linked microcrystalline celluloses such as croscarmellose sodium; alginates such as algic acid and sodium alginate; clays, such as bentonites; and effervescent mixtures.

The amount of disintegrant in the composition can vary, for example, from about 2 to about 15% by weight of the composition or from about 4 to about 10% by weight. Lubricants are substances that are added to a pharmaceutical formulation to make it possible for tablets, granules, etc. , after they have been compressed, they are released from the mold or die reducing friction or wear. Examples of lubricants useful in pharmaceutical dosage forms include boric acid, sodium benzoate, sodium acetate, sodium chloride, and the like. Lubricants are usually added in the last step before compressing the tablet, since they may be present on the surfaces of the granules and between them and the pieces of the tablet press. The amount of lubricant in the composition may vary, for example, from about 0.1 to about 5% by weight of the composition, from about 0.5 to about 2%, or from about 0.3 to about 1.5% by weight. The amount of compound or salt of the invention in a dosage unit can generally be varied or adjusted from about 1.0 milligram to about 1,000 milligrams, from about 1.0 to about 900 milligrams, from about 1.0 to about 500 milligrams. milligrams, or from about 1 to about 250 milligrams, according to the particular application and potency of the compound.

The actual dose used can be varied depending on the age, sex, weight of the patient, and the severity of the condition being treated. Pharmaceutical compositions formulated for oral administration are often preferred. These compositions contain between 0.1 and 99% of a compound of the invention and usually at least about 5% (% by weight) of a compound of the invention. Some embodiments contain from about 25% to about 50% or from 5% to 75% of a compound of the invention. Liquid Formulations The compounds of the invention can be incorporated into oral liquid preparations such as aqueous or oily suspensions, solutions, emulsions, syrups, tinctures, syrups, or Ixires, for example. Moreover, formulations containing these compounds can be presented as a dry product, for example as granules or powders, for constitution with water or other suitable vehicle before use. Typical carrier components for syrups, elixirs, emulsions and suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol and water. The liquid preparations may contain conventional additives, such as suspending agents (for example, sorbitol syrup, methyl cellulose, glucose / sugar, syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum gel stearate, and hydrogenated edible fats), emulsifiers (e.g., lecithin, sorbitan monooleate or acacia), non-aqueous vehicles, which may include edible oils (e.g., almond oil, fractionated coconut oil, silyl esters, propylene glycol and ethyl alcohol), and preservatives (for example, methyl or propyl p-hydroxybenzoate and sorbic acid). Oral formulations may contain demulcent, flavoring agents, sweetening agents, such as sucrose or saccharin, flavor dissimulating agents, and coloring agents. Suspensions Aqueous suspensions contain the material or active materials in admixture with suitable excipients for the manufacture of aqueous suspensions. These excipients are suspending agents, for example AVICEL RC-591, sodium carboxymethylcellulose, methylcellulose, hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and acacia gum; dispersing or wetting agents, for example lecithin and polysorbate 80. The aqueous suspensions may also contain one or more preservatives, for example ethyl, n-propyl p-hydroxybenzoate, methyl parabens, propyl parabens, and sodium benzoate. Oily suspensions may be formulated by suspending the active ingredients in a vegetable oil, for example, peanut oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. Oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Agents can be added sweeteners such as those discussed above, and flavoring agents, to provide palatable oral preparations. These compositions can be preserved by the addition of an antioxidant, such as ascorbic acid. Emulsions The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase can be a vegetable oil, for example olive oil or peanut oil, or a mineral oil, for example liquid paraffin or mixtures thereof. Suitable emulsifying agents can be gums of natural origin, for example gum acacia or gum tragacanth, phosphatides of natural origin, for example soybeans, lecithin, and partial esters or esters from fatty acids and hexitol, anhydrides, for example monooleate sorbitan and condensation products of said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. tablets v Capsules Tablets commonly contain conventional pharmaceutically compatible adjuvants, such as calcium carbonate, sodium carbonate, mannitol, lactose and cellulose; binders such as starch, gelatin and sucrose; disintegrants such as starch, alginic acid and croscarmellose; lubricants such as magnesium stearate, stearic acid and talc. Glidants such as silicon dioxide can be used to improve the flow characteristics of the powder mixture. Can it be added dyeing people, such as the dyes of the FD &C, to improve the appearance. Sweeteners and flavoring agents, such as aspartame, saccharin, menthol, peppermint, and fruit flavors, are useful adjuvants for chewable tablets. Capsules (including programmed release and prolonged release formulations) commonly contain one or more of the solid diluents described above. The selection of carrier components often depends on secondary considerations such as flavor, cost and storage stability. These compositions can also be coated by conventional methods, commonly with pH or time dependent coatings, such that the compound is released into the subject's gastrointestinal tract in the vicinity of the desired topical application, or at various times to prolong the desired action. These dosage forms commonly include, not limited thereto, one or more of cellulose acetate phthalate, pqlivinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, ethyl cellulose, Eudragit coatings, waxes and shellac. Formulations for oral use may also be presented as soft or hard capsule caps. A capsule is a dosage form that constitutes a special container or enclosure containing an active agent. The active agent may be present in solid, liquid, gel or powder form, or in any other pharmaceutically acceptable form. A capsule shell can be made of methylcellulose, polyvinyl alcohols, or denatured gelatins or starch or other material. Hard capsule shells are commonly made from combinations of bone gelatin and pig skin with relatively high gel strength. Covers for soft capsules are often made from animal or vegetable jellies. The capsule alone may contain small amounts of dyes, opacifying agents, plasticizers and preservatives. The active agent in a capsule can be mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or in the case of soft gelatin capsules the active ingredient can be mixed with water or an oily medium, for example, peanut oil, liquid paraffin or olive oil. Injectable and parenteral formulations The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension can be formulated according to the known art using those dispersing or wetting agents and suspending agents that have been mentioned above. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be used are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspension medium. For For this purpose, any combination of fixed oil, including synthetic mono- or diglycerides can be employed. In addition, fatty acids such as oleic acid are useful in the preparation of injectables. The compounds of the invention can be provided parenterally in a sterile medium. Parenteral administration includes subcutaneous, intravenous, intramuscular, intrathecal injection, or infusion techniques. The drug, depending on the vehicle and concentration used, may be suspended or dissolved in the vehicle. Advantageously, adjuvants such as local anesthetics, preservatives and buffering agents can be dissolved in the vehicle. In compositions for parenteral administration, the carrier commonly constitutes at least about 90% by weight of the total composition. Formulations packaged The invention includes packaged pharmaceutical combinations. These packaged combinations include a compound of Formula I in a container. The container may further include instructions for using the combination to treat or prevent a viral infection, such as a Hepatitis C infection, in a patient. The packaged pharmaceutical composition may include one or more additional active agents. Methods for treatment The invention includes methods to prevent and treat infections by Hepatitis C, providing an effective amount of a compound of the invention to a patient who is at risk of suffering from Hepatitis C infection or who is infected with a hepatitis C virus. The pharmaceutical combinations described herein are useful for preventing and treating infections for Hepatitis C in patients. An effective amount of a pharmaceutical combination of the invention may be an amount sufficient to (a) prevent hepatitis C from occurring or a symptom of hepatitis C in a patient who may be predisposed to hepatitis C but who has not yet been diagnosed as having has it or prevent diseases that may be associated with or caused by a primary Hepatitis C infection (such as liver fibrosis that may result in the context of chronic HCV infection); (b) inhibit the progression of hepatitis C; and (c) causing a regression of the Hepatitis C infection. An amount of an effective pharmaceutical composition to inhibit the progression or cause a regression of hepatitis C includes an effective amount to stop the worsening of hepatitis C symptoms or reduce the symptoms experienced by a patient infected with the hepatitis C virus. Alternatively a high in the progression or regression of hepatitis C may be indicated by any of several markers for the disease. For example, a lack of increase or reduction in the viral load of viral hepatitis C or a lack of increase or decrease in the amount of HCV antibodies in Circulation in the blood of a patient are markers of a breakthrough in the progression or regression of Hepatitis C infection. Other markers of hepatitis C disease include aminotransferase levels, particularly levels of the liver enzymes AST and ALT. Normal levels of AST are from 5 to 40 units per liter of serum (the liquid part of the blood) and normal levels of ALT are from 7 to 56 units per liter of serum. These levels will commonly be elevated in a patient infected with HCV. The regression of the disease will usually be marked by the return of AST and ALT levels to the normal range.

Symptoms of hepatitis C that may be affected by an effective amount of a pharmaceutical combination of the invention include decreased liver function, fatigue, flu-like symptoms: fever, cold, muscle aches, joint pain and headaches , nausea, aversion to certain foods, unexplained weight loss, psychological disorders including depression, tenderness in the abdomen and jaundice. "Liver function" refers to a normal function of the liver, including, but not limited to, a synthetic function that includes the synthesis of proteins such as serum proteins (eg, to buffalo, coagulation factors, alkaline phosphatase, aminotransferases (eg. example, alanine transaminase, aspartate transaminase), 5'-nucleosidase, and glutaminyltranspeptidase, etc.), bilirubin synthesis, cholesterol synthesis, and bile acid synthesis; a metabolic liver function, including metabolism of carbohydrates, amino acid and ammonia metabolism, hormonal metabolism, and lipid metabolism; detoxification of exogenous drugs; and a hemodynamic function, including visceral and portal hemodynamics. An effective amount of a combination described herein will also provide a sufficient concentration of the active agents in concentration when administered to a patient. A sufficient concentration of an active agent is a concentration of the agent in the patient's body necessary to prevent or combat the infection. Such an amount can be determined experimentally, for example by analyzing the blood concentration of the agent, or theoretically, by calculating the bioavailability. The amount of an active agent sufficient to inhibit viral infection in vitro can be determined with conventional analysis to determine viral infectivity, such as a replicon-based assay, which has been described in the literature. The invention also includes the use of pharmaceutical compositions containing a compound of the invention and at least one additional active agent in prophylactic therapies. In the context of prophylactic or preventive treatment, an effective amount of a compound of the invention is an amount sufficient to significantly decrease the risk of the patient of contracting a Hepatitis C infection. Treatment methods include providing certain amounts of doses of a composed of the invention and the at least an additional active agent to a patient. The dose levels of each active agent from about 0.1 mg to about 40 mg per kilogram of body weight per day are useful in the treatment of the conditions indicated above (approximately 0.5 mg to approximately 7 g per patient per day). The amount of active ingredient that can be combined with the carrier materials to produce a single dose form will vary depending on the patient being treated and the particular administration form. Dosage unit forms will generally contain between about 1 mg to about 500 mg of each active agent. In some embodiments, it is provided daily from 25 mg to 500 mg, or from 25 mg to 200 mg of a compound of the invention to a patient. When the additional active agent is NM 283 (valopicitabine), the patient is commonly given from 1000 mg to 1000 mg / day, or from 200 mg to 800 mg / day, or from 200 to 400 mg / day from either of these agents. When the additional active agent is VX-950, it is administered from 1000 mg to 3750 mg / day, or from 1200 mg to 1800 mg / day to the patient. Treatment regimens in which VX-950 is an additional active agent and administered to a patient from about 350 to about 450 mg or from about 700 to about 800 mg of VX-950 three times per day or administer about 350 to about 450 mg or about 700 to about 800 mg every 1 2 hours are particularly included in the invention. The dose frequency may also vary depending on the compound used and the particular disease treated. However, for the treatment of most infectious disorders, a dose regimen of 4 times daily or less is preferred and a dose regimen of 1 or 2 times daily is particularly preferred. It will be understood, however, that the specific dose level for any particular patient will depend on a variety of factors, including the activity of the specific compound employed, age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, combination of drug and the severity of the particular disease that is under therapy. Combination Methods The invention includes methods for treatment in which a compound or salt of the invention is provided together with one or more additional active agents. In some embodiments, the active agent (or agents) is an inhibitor of HCV protease or HCV polymerase inhibitor. For example, the protease inhibitor can be telaprevir (VX-950) and the polymerase inhibitor can be valopicitabine, or NM 1 07, the active agent in which valopicitabine is converted in vivo. In some embodiments, the second active agent is ribavirin, interferon, or conjugate Peg-interferon alpha.

According to the methods of the invention, the compound of the invention and an additional active agent can be: (1) formulated together and administered or delivered simultaneously in a combined formulation; (2) supplied by alternation or in parallel as separate formulations; or (3) by any other combination therapy regimen known in the art. When supplied in alternation therapy, the methods of the invention may include administering or delivering the compound of the invention and an additional active agent sequentially, for example, in solution, emulsion, suspension, tablets, pills or capsules, separately, or by different injections in separate syringes. In general, during alternation therapy, an effective dose of each active ingredient is administered sequentially, i.e., in series, while in concurrent therapy, effective doses of two or more active ingredients are administered together. Various sequences of intermittent combination therapy may also be used. In some embodiments, the method of treatment includes providing a patient with a compound of Formula I and an interferon such as a pegylated interferon or interferon gamma. The interferon may be the only compound supplied with the compound of the invention or may be delivered with an additional active agent other than an interferon. The treatment methods of the invention and the pharmaceutical combinations include any of the compounds of the invention or a combination of the following compounds and substances as an additional active agent: I caspase inhibitors: I DN 6556 (Idun Pharmaceuticals) Cyclophilin inhibitors: N IM81 1 (Novartis) and DEB I O-025 (Debiopharm) Inhibitors of cytochrome P450 monooxygenase: ritonavir (WO 94/1 4436), ketoconazole, troleandomycin, 4-methyl pyrazole, cyclosporin, clomethiazole, cimetidine, itraconazole, fluconazole, miconazole, fluvoxamine, fluoxetine, nefazodone, sertraline, indinavir, nelfinavir, amprenavir, fosamprenavir, saquinavir, lopinavir, delavirdine, erythromycin, VX-944, and VX-497. Preferred CYP inhibitors include ritonavir, ketoconazole, troleandomycin, 4-methyl pyrazole, cyclosporin and clomethiazole. Glucocorticoids: hydrocortisone, cortisone, prednisone, prednisolone, methylprednisolone, triamcinolone, parametasone, betamethasone, and dexamethasone Hematopoietin: hematopoietin-1 and hematopoietin-2. Other members of the hematopoietin superfamily, such as various colony stimulating factors (eg (eg G-CSF, GM-CSF, M-CSF), Epo, and SCF (stem cell factor) Homeopathic Therapies: Thistle Mariano, Silymarin, ginseng, glycyrrhizin, licorice, Schisandra, vitamin C, vitamin E, beta carotene, and selenium Immunomodulatory compounds: thalidomide, I L-2, hematopoietins, inhibitors of IM PDH, for example Merimepodib (Vértex Pharmaceuticals Inc.), interferon, including natural interferon (such as OMNIFERON, Viragen and SUMIFERON, Sumitomo, a mixture of natural interferons), natural interferon alpha (ALFERON, Hemispherx Biopharma, Inc.), interferon alpha and lymphoblastoid cells ( WELLFERON, Glaxo Wellcome), oral interferon alfa, Peg-interferon, Peg-interferon alfa 2a (PEGASYS, Roche), recombinant alpha interferon 2a (ROFERON, Roche), inhaled interferon alfa 2b (AERX, Aradigm), Peg-interferon alfa 2b (ALBUFERON, Human Genome Sciences / Novartis, PEGINTRON, Schering), recombinant alpha interferon 2b (INTRON A, Schering), pegylated interferon alpha 2b (PEG-INTRON, Schering, VIRAFERONPEG, Schering) interferon beta-1a (REBIF, Serono, Inc. and Pfizer), consensus interferon alpha (INFERGEN, Valeant Pharmaceutical), interferon gamma-Ib (ACTIMMUNE, Intermune, Inc.), non-pegylated interferon alpha, interferon alpha, and its analogs, and synthetic thymosin alfa 1 (ZADAXIN, SciClone Pharma ceuticals Inc.) Immunosuppressants: sirolimus (RAPAMUNE, Wyeth). Interleukins: (IL-1, IL-3, IL-4, IL-5, IL-6, IL-0, IL-11, IL-12), LIF, TGF-beta, TNF-alpha) and other factors low molecular weight (for example AcSDKP, pEEDCK, thymic hormones and minicitocins). Interferon Enhancers: EMZ702 (Transition Therapeutics). IRES inhibitors: VGX-410C (VGX Pharma). Monoclonal and polyclonal antibodies: XTL-6865 (XTL), HuMax-HepC (Genmab), Immunoglobulin against Hepatitis C (human) (CIV ACER, Nabi Biopharmceuticals). Nucleoside analogues: Lamivudine (EPIVIR, 3TC, GlaxoSmithKine), MK-0608 (Merck), zalcitabine (HIVID, Roche US Pharmaceuticals), ribavirin (including COPEGUS (Roche), REBETOL (Schering), VILONA (ICN Pharmaceuticals, and VIRAZOL ( ICN Pharmaceuticals), and viramidine (Valeant Pharmaceuticals), a ribavirin amidine prodrug It is also possible to use combinations of nucleoside analogues Non-nucleoside inhibitors: PSI-6130 (Roche / Pharmasset), delaviridin (RESCRIPTOR, Pfizer), and HCV- 796 (Viropharm) P7 protein inhibitor: amantadine (SYMMETREL, Endo Pharmaceuticals, Inc.) Polymerase inhibitors: NM283 (valopicitabine) (Idenix) and NM 107 (Idenix) Protease inhibitors: BELN-2061 (Boehringer Ingelheim) , GW-433908 (prodrug of Amprenavir, Glaxo / Vertex), indinavir (CRIXIVAN, Merck), ITMN-191 (Intermune / Array Biopharma), VX950 (Vertex) and combinations containing one or more of the above protease inhibitors. RNA interference: SIRNA-034 RNAi (Sirna Therapeutics) Therapeutic vaccines: IC41 (Intercell), IMN-0101 (Imnogenetics), Gl 5005 (Globeimmune), Chronvac-C (Tripep / Inovio), ED-002 (Imnogenetics), Hepavaxx C (ViRex Medical) TNF agonists: adalimumab (HUMIRA, Abbott), entanercept (ENBREL, A mgen and Wyeth), infliximab (REMICADE, Centocor, Inc.) Tubulin inhibitors: Colchicine Sphinqosine-1-phosphate receptor modulators: FTY720 (Novartis) TLR agonists: ANA-975 (Anadys Pharmaceuticals), TLR7 agonist (Anadys Pharmaceuticals), CPG 1 01 01 (Coley), and agonists TLR9 including CPG 7909 (Coley) Diclofilin inhibitors: N IM81 1 (Novartis) and DEB IO-025 (Debiopharm) Patients receiving anti-hepatitis C medications are commonly given interferon along with another active agent. Thus, methods for treatment and pharmaceutical combinations in which a compound of the invention is provided together with an interferon, such as pegylated interferon alpha 2a, as additional active agents, are included as embodiments. Similarly, pharmaceutical methods and combinations in which ribavirin is an additional active agent are provided herein. Examples Abbreviations The following chemical abbreviations are used in Example 1.

The additional abbreviations used in these examples will be familiar to those trained in the technique of organic chemical synthesis. CDI 1, 1 '- Carbonyldiimidazole DBU Diazabicyclo [5.4.0] u ndec-7-ene DCM Dichloromethane DEEA?,? - Diisopropylethyl amine DMF Dimethyl formamide HATU 0- (7-azabenotriazole-1, 1, 3,3-tetramethyluronium HBTU 0- (IH-Benzotriazol-1-yl) / v, / V, / V ', A /' - tetramethyluronium NMM N-methylmorpholine RC Ring closure methionhesis TEA Triethylacetate TFA Trifluoroacetic acid Example 1. Synthesis of acid 1- (f2S.4R> -1 - ((S ^ -2-tert-butyl -4-oxo-4- (piperidin-1-yl) butanoin-4- (7-methoxy-2-phenylquinoltn-4-yloxn pyrrolidine-2-carboxamido) -2-vinylcyclopropanecarboxylic Step 1. Preparation of N- (c) clopropylsulfonyl) -1- (BOC-arnino) -2-vinylcyclopropanecarboxamide Dissolve CDI (2.98 g, 18.4 mm, 1.1 eq) in ethyl acetate. N-Boc-cyclopropylvinyl acid (3.8 g, 16.7 mm, 1.0 eq) is added, prepared by the procedure provided by Beaulieu, P.L. et al. (J. Org. Chem. 70: 5869-79 (2005)) to the CDI / ethyl acetate mixture and stirred at room temperature until the initial material is consumed. Cyclopropyl sulfonamine (2.2 g, 18.4 mm, 1.1 eq) is added to this mixture followed by DBU (2.1 ml, 20.5 mm, 1.23 eq) and the mixture is stirred at room temperature for 2 h. The final treatment and purification by chromatography on silica gel provide 2 g of compound 2. Step 2. Preparation of 2- (1- (cyclopropylsulfonylcarbamoyl-2-vinylcyclopropylcarbamoyl) -4- (7-methoxy-2-phenylquinoline- 4-Ixyloxy) pyrrolidine-1-carboxylate of (2S, 4R) -tert-butyl v (2S, 4R) -N- (1 - (cyclopropylsulfonylcarbamoyl) -2-vinylcyclopropyl) -4- (7-methoxy-2-phenylquinoline -4-iloxQpirrolidina-2-carboxarnida Compound 1 (4.3 g, 9.3 mmol, 1.1 eq), prepared according to the methods given in WO 02/060926, in DMF, is stirred with 0- (Benzotriazol-1-yl) hexafluorophosphate, / S /, A / ', / \ /' - Tetramethyluronium (4.1 g, 10.5 mmol, 1.3 eq) for 30 minutes, followed by the addition of cyclopropylamine 2 (1.92 g, 8.3 mmol, 1.0 eq) and N-methylmorpholine (2.52 g) , 25.0 mmol, 3.0 eq). The mixture is stirred overnight and the solvent is removed under reduced pressure. He The resulting residue is diluted with ethyl acetate and washed with saturated aqs NaHCO3. The organic solvent is dried over MgSO4 and concentrated under reduced pressure to produce crude, which is used for the next step without further purification. Compound 3 in 1 mL of dry CH2Cl2 is treated with 5 mL of TFA and stir overnight. The solvent is removed and the residue recrystallized from ethyl acetate to yield 4.1 2 g of Compound 4 (61% yield in two steps). Step 3. Preparation of (3S) -3 - ((2S.4R) -2- (1 - (Cyclopropylsulphoncarbamoyl) -2-vinylcyclopropylcarbamoyl> 4- (7-methyloxy-2-phenylquinolin-4-yloxy) acid ) pyrroiidine-1 -carbonyl) -4.4- dimethylpentanoic Acid 5 (58 mg, 0.25 mmol, 1.2 eq), prepared by the procedure provided by Evans, D.A. , et al. (J. Org. Chem. 64: 641 1-6417 (1999)) in 1.2 mL of DM F is stirred with 4 (1.38 mg, 0.21 mmol), HATU (160 mg, 0.42 mmol, 2.0 eq). , and DIEA (0.63 mmol, 3.0 eq) during the night. The mixture is subjected to purification with HPLC to produce 121 mg of 6 (yield 77%), which is further treated with 0.5 mL of TFA in 1.0 mL of DCM overnight. The solvent was removed to provide Compound 7 in 100% yield.

Step 4. Preparation of 2S.4R) -1 - ((S) -2-tert-Butyl-4-oxo-4- (piperidin-1-inbutaneyl> -N- (1- (cyclopropylsulfonylcarbamoyl) -2- vinylcyclopropyl -4- (7-methoxy-2-phenylquinolin-4-yloxy) pyrrolidine-2-carboxamide Acid 7 (0.15 mmol) in 1.0 ml_ DMF is stirred with piperidine (excess, 0.6 mmol, 4 eq), HATU (115 mg, 0.3 mmol, 2.0 eq), and DIEA (0.45 mmol, 3.0 eq) for 4 hours. The mixture is subjected to purification with HPLC to yield 77.1 mg of 8. Step 5. Preparation of (3S) -3-f (2S.4R) -2- (1 - (ethoxycarbonyl) -2-vinylcyclopropylcarbamoyl) -4- acid (7-methoxy-2-phenylquinolin-4-yloxy) pyrrolidine-1-carbonin-4,4-dimethylpentanoic acid 10 11 The acid 5 (105 mg, 0.46 mmol, 1.2 eq) in 1.2 ml_ of DMF is stirred with 9 (202 mg, 0.38 mmol), HATU (290 mg, 0.76 mmol, 2.0 eq), and DIEA (1.2 mmol, 3.0 eq) during the night. The mixture is subjected to purification with H PLC to produce 204.3 mg 1 0 (yield 75%), which is further treated with 0.5 mL of TFA in 1.0 mL of DCM overnight. The solvent is removed to provide 1 1 in 1 00% yield.

Step 6. Preparation of the final product The acid 1 1 (30 mg, 0.045 mmol) in 1.0 mL of DMF is stirred with pepridine (0.27 mmol, 6 eq), HATU (34 mg, 0.09 mmol, 2.0 eq), and DI EA (0.14 mmol, 3.0 eq) for 2 hours. The mixture is subjected to purification with HPLC to yield 21.2 mg of 1 2 (65% yield), which is hydrolyzed in methanol with 2N NaOH for 6 hours. The mixture is acidified with 6N HCl and subjected to purification with HPLC to yield 7.6 mg of 1. Example 2. Synthesis of macrocyclic compounds General procedures Procedure 1. Deprotection reaction (Conversion of N-Boc to amine or t-butyl ester to carboxylic acid) TFA (3-4 mL) is added to a solution of Boc-protected starting material (1 mmol) or t-butyl ester in anhydrous DCM (7 mL) at room temperature. The reaction is monitored with LC / MS and TLC. After 1 -3 hours, the reaction mixture evaporated under Reduced pressure until dry. The crude product is used for the next step of the reaction without further purification. Procedure 2. Amide Formation N-methylmorpholine (2 mmol) and HBTU (1.2 mmol) are added in one portion at room temperature to a solution of acid (1 mmol) in anhydrous DMF (10 mL). After stirring at room temperature for 10 minutes, amine (1 mmol) is added in one portion and then stirred overnight. The reaction mixture is poured into ice water and extracted with ethyl acetate (100 ml_). The organic layer is washed with H20, brine, and dried over anhydrous MgSO4. The residue is filtered and evaporated in vacuo to dryness. The crude product is purified by flash chromatography on silica gel (hexane-ethyl acetate 100: 0 to 50:50) to give the desired product. Procedure 3. RCM catalysed by Grubbs second catalyst (CAS Reg. No. 246047-72-3) or second Hovevda-Grubbs catalyst (CAS Req. No. 301224-40-8) A mixture of starting material (di-olefin, 1 mmol), catalyst (5-30 mol%) in 1,2-dichloroethane is degassed and heated to 1110 ° C for 1-2 ~ 24 hours under an argon atmosphere. The reaction is monitored by LC / MS and TLC. The reaction mixture is evaporated to dryness under reduced pressure. The crude product is purified by flash chromatography on silica gel (hexane-ethyl acetate 100: 0 to 50:50) to give the desired product. Procedure 4. Hydrolysis of esters LiOH hydrate (6 equiv.) Is added in one portion at room temperature to the solution of ester (1 mmol) in THF (5 mL), methanol (2.5 mL) and water (2.5 mL), and then the mixture of The reaction is stirred overnight. After the reaction is complete (by LC / MS), it is cooled to 0 ° C and acidified to pH ~ 2 and extracted with DCM (20 mL x 2). The reaction is dried over MgSO4, filtered, and evaporated to dryness under reduced pressure. The crude product is purified by flash chromatography on silica gel (hexane-ethyl acetate 100: 0 to 20:80) to give the desired product. Esq uema 1 22 The compound 21 is prepared by processes 1 and 2 from starting material 14 and amino acid 20. MS (M ++ 1) 754. Compound 22 is prepared by the procedure step 3. MS (M ++ 1) 726. Compound 23 is prepared by procedures 1 and 2. MS (M ++ 1) 737. Compound 24 is prepared by method 4. MS (M ++ 1) 709. Scheme 2. Synthesis of Compounds 34 and 35 Compound 29 is prepared by process 4 from initial material 28. Compound 30 is prepared by the procedure set forth in step 2 with starting material 29. Compound 31 is prepared by the procedure set forth in Steps 1 and 2 with starting material 30. Compound 33 is prepared by the procedure set forth in step 4 with starting material 28 and 32. Compounds 34 and 35 are prepared by the method set forth in step 3. After RCM, the reaction mixture is separated by prep-TLC (hexane-ethyl acetate 1: 1) to yield compounds 34 and 35. MS (M ++ 1) = 81 2 Preparation of intermediate products 20 and 32 Step 1 . 8-NONenoic acid (1.56 g, 10 mmol) is placed in a 1 00 ml bottle, anhydrous ether (35 mL) is added under N2, cooled to 0 ° C, TEA (1.6) is added. g, 16 mmol), followed by pivaloyl chloride (1.26 g, 1 0.5 mmol) per drop. The ice bath is removed and the reaction mixture is stirred at room temperature for 1 hour. The resulting suspension is cooled to 0 ° C and filtered in a 250 mL flask under N2 (washed twice with anhydrous ether 10 mL x 2). The filtrate is cooled to -78 ° C and diluted with anhydrous THF (25 mL). A few crystals of 1,1-phenanthroline or a solution of (S) (-) - 4-benzyl-2-oxazolidinone in THF (25 mL) are added. The The solution is cooled to -78 ° C and a solution of M-BuLi (1.6M in hexane, 6.5 mL, 1.4 mmol) is added dropwise until the red color persists for 10 min. This solution is added to the mixed anhydride solution cooled to -78 ° C for 20 min by cannula. The resulting mixture is stirred at -78 ° C for a further 30 min, then poured into saturated N H 4 Cl, the organic layer is separated, the aqueous layer is extracted with ether (50 mL, 3X). The combined organic layers are washed with brine and dried over MgSO4, filtered, concentrated under reduced pressure to dryness. The crude product is purified by flash chromatography (hexane-ethyl acetate 1 00: 0-1 00:20) to give 3.01 g of 26 (95%).

Step 2. A solution of 26 (3.01 g, 9.6 mmol) in THF anhydrous was cooled to -78 ° C, then 2.0 m NaN (TMS) 2 solution in hexane (5.76 mL) was added dropwise during 1 0 min. After 30 min, t-butyl bromoacetate was added dropwise at -78 ° C. The reaction mixture was stirred at -78 ° C for 2 hours. The reaction was monitored by LC / MS and TLC. The reaction was quenched with 1.0% KHS04 for pH ~4 ~ 6, extracted with ethyl acetate, the organic layer was washed with H20, brine, dried over MgSO4, filtered, evaporated under reduced pressure to dry crude product was purified by chromatography on silica gel (hexane-ethyl acetate 100: 0-100: 20) to give compound 14. Step 3. H202 (50%, 0.9 mL) is added dropwise during 5 minutes to 0 ° C, followed by a solution of LiOH (0.2 g in 2 mL of H20). The reaction mixture is added to a solution of (1.05 g, 2.44 mmol) in TH F / H20 (5: 1, 24 ml_). The mixture is stirred at 0 ° C for 1 h and then cooled rapidly by the addition of an aqueous solution of sodium thiosulfate (10 ml) while keeping the temperature below 20 ° C. The mixture is extracted with ethyl acetate (is discarded) and the aqueous phase is acidified to a pH ~ 2 with solid citric acid and extracted with ethyl acetate.The combined organic phase is washed with brine, dried over anhydrous sodium sulfate and the solvent is added. Remove under reduced pressure The residue is purified by column chromatography on silica gel, eluting with a gradient system of hexane: ethyl acetate (10000) to 50:50 to yield the desired compound 20 (503 mg). Step 4. Compound 36 is prepared by procedure 1. Step 5. Compound 37 is prepared by procedure 2. Step 6. Compound 32 is prepared from 37 by the procedure of step 3 for the preparation of compound 20. Example 3. Other p peptides substituted tertiary ami na NQ Estruc ira Ncrrtxe K50 phen'lquinoline-4-ylod) 5,6-dcM > 1,2,3,5,6,7,8,9, ^ 11,133,14,143,15,16,16 55 a-heacfecah (l adopOpaieJpirrciai (2- * 5 ai [i, 4idazaddcpentactecina- 4a- cartxjdlatD de (2R, 6R, 13aS, i4aR, i6as, Z) - ethyl áddo1 - ((2S, 4R) - - ((9-2-tErt-butih4- (3 (4- dh '(OCOCMndir ^ (2H) Hl) -CK0butara 56 4- (7-rreb3d-2-fienllind Na-4- ** 10 ICKDpima¡dna-2-cartxjGmctí-2- ádd0l - ((2S) 4R) -1 - ((9-2-tErt-lXltÍI-4- (3l4-dl dOiscxMinda-2 (iH) -l) -4- CKCbutandl) -4- (7-r ^ 57 * 15 fertlciuind¡ria-4-ilcM) prTd¡dna-2- cartxjGrrictí-2- \? rilad opO nocartxjíliro (2R, 6R, 1S3S, 14aR, 16aS ^) - - (dd pOpisüfail) -2- (7-mBta < i-2- ?????? μ ?????? - 4- ?? ) -5 (? 6 < ?? 6- (2- or «2- { Piperidna-l-il) eül) - *** 58 20 1,2,3,5,6,7,8,9,1011,133,14,143,15,16,16 a4T © adecah < * oadcpOr dp ^ al [i, 4idazaa "dop3tactea'na- 4a- cartoorrida 25 (2 ^ 6 ^ 1335.1 ^, 1635.3-1 ^ - (ddqxoplsui onD-2- (7-rr¾tei i-2- ferilqu¡rxa¡na-4-¡MCM) -¾16-dci < < > 6- (2-CK 2- (peridna- -DetíD- 59 *** 1,2,3,5,6,7,8,9,10,11,15a, 14,1-¾, 15 , 16,16a- or heactecartct ddopn¾B [dp "rTdcti, 2- a [l, 4idazEddopertadecin-i4a-aitoarrida ((2S, 4l¾-1 - ((S) -2-tm-IXltih4-CM - (pperiodine iHl) butanofl) -N - ((Rt2S) - - (ddopOp'lsüfGrilcartHral) -2- T0 *** \ r "rilddo | JOq'l) -4- (7-rTtíD > á-2- fmilc ndira- 4-yl (M) piTiDrin-2-ortxjcanide Example 4. Analysis to identify compounds that inhibit HCV replication The compounds claimed here are tested for their ability to inhibit the viral replication of the hepatitis C replicon in cultured cells in which the replicon of the HCV HCV has been incorporated. The replicon of the HCV system was described by Bartenschiager, et. al (Science, 285, pp. 1 10-1 1 3 (1 999)). The replicon system is predictive of anti-VH C activity in vivo; the compounds that are active in beings humans uniformly show the activity in the replicon analysis. In this analysis the HCV replicon containing cells are treated with different concentrations of the test compound establishing the ability of the test compound to suppress the replication of the HCV replicon. As a positive control, cells containing HCV replicon are treated with different concentrations of interferon alpha, a known inhibitor of HCV replication. The replicon analysis system includes Neomycin Phosphotransferase (NPT) as a component of the replicon itself in order to detect the transcription of the replicon gene products in the host cell. The cells in which the HCV replicon is actively replicated have high levels of TPN; the level of TPN is proportional to the replication of HCV. Cells in which the HCV replicon is not replicating also have low levels of TPN and therefore do not survive when treated with Neomycin. The level of N PT of each sample is measured using a captured ELISA. A protocol for testing the compounds for their ability to inhibit viral replication of the replicon cells cultured with the hepatitis C replicon in which the replicon construct has been incorporated is presented below. 4A. Replicon of HCV and replicon expression The HCV genome consists of a single ORF that encodes a protein of 3000 amino acids. The ORF is flanked on the 5 'side by a non-translated region that serves as an internal ribosome entry site (I RES) and on the 3' side by a highly conserved sequence necessary for viral replication (3'-NTR) . The structural proteins, necessary for viral infection, are located near the 5"end of the ORF.The nonstructural proteins, denominated NS2 through NS5B, constitute the rest of the ORF.The HCV replicon contains 5'-3 \ I RES from HCV, the neomycin phosphotransferase gene (neo), the I RES of the encephalomyocarditis virus, which directs the translation of the HCV NS3 sequences up to NS5B, and the 3 'NTR.The sequence of the HCV replicon has been deposited in GenBank (Accession No. AJ242652) The replicon is transfected into Huh-7 cells using standard methods, such as electroporation 4B Cell maintenance Equipment and materials include, but are not limited to, cells containing the replicon of HCV Huh-7, maintenance medium (DM EM (Eagle's Medium modified with Dulbecco) supplemented with 10% FBS, L-glutamine, non-essential amino acids, penicillin (1 00 units / mL), streptomycin (1 00 micrograms / mL), and 500 micrograms / mL of Geneticin (G41 8), detection medium (MS DM supplemented with 1.0% FBS, L-glutamine, non-essential amino acids, penicillin (1000 units / mL) and streptomycin (1000 micrograms / mL)), plates for culture from tissue of 96 receptacles (flat bottom), 96 receptacle plates (U bottom for drug dilution), interferon alpha for positive control, reagent for fixation (such as methanol: acetone), primary antibody (anti-N PTI l rabbit ), secondary antibody: Eu-N I 1, and enhancer solution. Cells containing the HCV replicon support high levels of replication of the viral RNA replicon when its density is appropriate. Over-confluence causes decreased replication of viral RNA. Therefore, the cells should be kept growing in the log phase in the presence of 500 micrograms / mL of G418. Generally, the cells should be passed twice a week in a 1: 4-6 dilution. Cell maintenance is performed as follows: The cells containing the HCV replicon are examined under a microscope to make sure that the cells are growing well. The cells are rinsed once with PBS and 2 mL of trypsin is added. The cell / trypsin mixture is incubated at 37 ° C in a CO 2 incubator for 3-5 minutes. After incubation, 10 mL of complete medium is added to stop the trypsinization reaction. The cells are gently blown, placed in a 1 5 mL tube and rotated at 1200 rpm for 4 minutes. The trypsin / medium solution is removed. Medium (5 mL) is added and the cells are mixed thoroughly. The cells are counted. The cells are then seeded in 96-well plates in a density of 6000-7500 cells / 1000 microlitres / receptacle (6-7.5 x 1 05 cells / 10 mL / plate). The plates are then incubated at 37 ° C in an incubator with 5% C02. The cells are examined under a microscope approximately 24 hours after sowing and before adding the drugs. If counting and dilution were performed correctly, the cells are 60-70% confluent and almost all cells should be joined and dispersed uniformly in the receptacle. 4C. Treatment of cells containing HCV replicon with the test compound Cells containing HCV replicon are rinsed with PBS only once; then 2 mL trypsin is added. The cells are incubated at 37 ° C in an incubator with 5% C02 for 3-5 minutes. 1 mL of complete medium is added to stop the reaction. The cells are gently blown, placed in a 1 5 mL tube and rotated at 1200 rpm for four minutes. The medium / trypsin solution is removed and 5 mL of medium (500 mL DM MS (high in glucose)) is added from the catalog of BRL # 1 2430-054; 50 mL of 10% FBS, 5% Geneticin G418 (50 mg / mL, catalog of BRL # 1 01 31 -035), 5 mL of non-essential amino acids M EM (1 00x BRL # 1 1 140-050) and 5 mL from pen-strep (BRL # 1 51 40-148). Cells and media are mixed carefully. Cells are plated with detection medium (500 mL of DMEM (BRL # 21063-029), 50 mL of FBS (BRL # 1 0082-1 47) and 5 mL of non-essential amino acid M EM (BRL # 1 1 140-050) to 6000- 7500 cells / 100 pL / receptacle of a 96-well plate (6-7.5x105 cells / 10 mL / plate). The plates are placed in an incubator at 37 ° C, 5% C02 overnight. 4D. Analysis The next morning, the drugs (test compounds or interferon alpha) are diluted in 96-well U-bottom plates with media or with DMSO / media, depending on the final concentration chosen for selection. They are generally applied for 6 concentrations of each test compound ranging from 10 micromolar to 0.03 micromolar. 100 pL of the dilution of the test compound is placed in receptacles of the 96-well plate containing the cells with HCV replicon. Drug-free medium is added to some receptacles as negative controls. It is known that DMSO affects cell growth. Therefore, if drugs diluted in DMSO are used, all receptacles, including the negative control, (only medium) and the positive control (interferon alpha), must contain the same concentration of DMSO, for the selection of simple dose. The plates are incubated at 37 ° C in a humidified environment with 5% C02 for days. On day 4, the NTPII analysis is quantified. The medium is poured from the plates and the plates are washed once in 200 pL of PBS. Then the PBS is decanted and the plates are tapped on paper towels to remove any remaining PBS. Cells are fixed in situ with 100 pL / methanol: acetone (1: 1) reservoir previously cooled (-20 ° C) and the plates are placed at -20 ° C for 30 minutes. The fixation solution is poured from the plates and the plates are allowed to air dry completely (approximately one hour). The appearance of the dried cell layer is recorded and the density of the cells in the toxic receptacles is graded by the naked eye. Alternatively, cell viability can be evaluated using the MTS analysis described below. The receptacles are blocked with 200 pL of blocking solution (1.0% FBS, 3% NGS in PBS) for 30 minutes at room temperature. The blocking solution is removed and 1 00 μ? of anti-NPTI l rabbit diluted 1: 1000 in blocking solution to each receptacle. The plates are then incubated 45-60 minutes at room temperature. After incubation, the wells are washed six times with PBS-0.05% Tween-20 solution. 1 μl of goat anti-rabbit conjugated with Europium (EU) diluted 1: 1 5,000 in blocking buffer is added to each receptacle, and incubated at room temperature for 30-45 minutes. The plates are again washed and 1 00 pL of enhancing solution (Perkin Elmer # 4001 -001 0) is added to each receptacle. Each plate is shaken (approximately 30 rpm) on a plate shaker for three minutes. 95 pL of each receptacle is transferred to a black plate; the EU signal is quantified in a plate reader Perkin-Elmer VICTOR (EU-Lance). The compounds shown in Example 3 have been tested in this analysis. Those that have an "*" in the EC50 column have an EC50 greater than 1 0 micromolar, those that have two (**) have an EC50 greater than 1 micromolar but less than 1 0 micromolar, and those with three (* **) have EC50 values of 100 nanomolar or less. Example 5. Cytotoxicity analysis To ensure that the decrease in replication of the HCV replicon is due to the activity of the compound against the HCV replicon rather non-specific toxicity analyzes are used to quantitate the cytotoxicity of the compound. 5A. Cellular protein albumin assay for cytotoxicity determination Measurements of cellular protein albumin provide a marker of cytotoxicity. The protein levels obtained from the cellular albumin assays can also be used to provide a reference normalization for the activity of the compounds. In protein albumin analysis, cells containing HCV replicon are treated for three days with different concentrations of helioxanthin; a compound that is known to be cytotoxic in high concentrations. The cells are lysed and the cell lysate is used to bind goat anti-albumin antibody bound to the plate at room temperature (25 ° C to 28 ° C) for 3 hours. Then the plate is washed 6 times with IX PBS. After unbound proteins are washed off, mouse monoclonal human serum anti-albumin is applied to fix the albumin on the plate. The complex is then detected using phosphatase-labeled mouse anti-IgG as a second antibody. 5B. Anis with MTS to detect cytotoxicity Cell viability can also be determined by cell proliferation analysis solution CELLTITER 96 AQU EOUS ONE (Promega, Madison Wl), a colorimetric analysis to determine the amount of viable cells. In this method, before fixing the cells, 10-20 μL · of MTS reagent is added to each receptacle according to the manufacturer's instructions, the plates are incubated at 37 ° C and read at OD 490 nm. During the incubation period the living cells convert the MTS reagent into a formazan product that is absorbed at 490 nm. Thus, the absorbance at 490 nm is directly proportional to the number of living cells in culture. - A direct comparison of the methods with cellular albumin and MTS for determining cytotoxicity can be obtained as follows: The cells are treated with different concentrations of test compound or helioxanthin for a period of three days. Prior to lysis for the detection of albumin as described above, the MTS reagent is added according to the manufacturer's instruction to each receptacle and incubated at 37 ° C and read at OD 490 nm. The quantification of cellular albumin is then carried out as described above.

Claims (1)

1. CLAIMS 1. A compound of the formula: or a pharmaceutically acceptable salt thereof, wherein - represents a single or double covalent bond, and the group contains 0 or 1 double bonds. R, is -NR10Rii, - (C = O) NR10Rn, - (C = S) NR10Rn, - (C = 0) R12, -SO2R12, - (C = 0) OR12, -0 (C = 0) R12, -ORi2, or -N (C = 0) R12, or R2 is hydrogen, d-Cealkyl, C3-C7cycloalkyl, heterocycloalkyl, (aryl) C0-C4alkyl; or Ri and R2 are taken together to form an optionally substituted 5 to 7 membered heterocyclic ring containing 0 or 1 additional N, S or O atoms, or an optionally substituted 5 to 7 membered heterocyclic ring containing 0 or 1 atoms additional N, S or O fused with a 5- or 7-membered carbocyclic or heterocyclic ring optionally substituted. R3. R, R5. R6, R7, and Re independently are (a) hydrogen, halogen or amino, or (b) CT-Cealkyl, C2-C6alkenyl, (C3-C7cycloalkyl) Co-C4alkyl, (C3-C7cycloalkenyl) C0-Calkyl, (heterocycloalkyl) ) C0-C alkyl, C2-C6alkanoyl, or mono- or di- C ^ Cealkylamino, each of which is optionally substituted; or R3 and R4 may be attached to form an optionally substituted 3 to 7-membered cycloalkyl ring or an optionally substituted 3 to 7 membered heterocycloalkyl ring containing 1 or 2 heteroatoms independently selected from N, S, and O. R5 and 6 may be joined to form an optionally substituted 3 to 7 membered cycloalkyl ring or an optionally substituted 3 to 7 membered heterocycloalkyl ring containing 1 or 2 heteroatoms independently selected from N, S, and O. R7 and R8 may be attached to form a optionally substituted 3 to 7 membered cycloalkyl ring or optionally substituted 3 to 7 membered heterocycloalkyl ring containing 1 or 2 heteroatoms independently selected from N, S, and O. R 5 is a saturated or unsaturated hydrocarbon chain of 7 to 11 atoms of carbon that is (i) covalently attached to R7, wherein R7 is a methylene group or R5 is a saturated or unsaturated hydrocarbon chain e 7 to 11 carbon atoms that is (ii) covalently linked to an optionally substituted cycloalkyl ring, formed by R7 and R8 which are attached to form a 3- to 7-membered cycloalkyl ring optionally substituted; and R6 is hydrogen, CT-Cealkyl, or (C3-C7cycloalkyl) C0-C2alkyl; T is a tetrazole group bound by its carbon atom, or T is a group of the formula: R9 is hydroxyl, amino, -COOH, -NR10Rn, -ORi2, -SR12, -NR10 (S = O) R11) -NR10SO2Rii, -NR ^ SONR R ^, -NRnoSOzNRnR ^, - (C = O) OR10, - NR10 (C = O) OR11, or - CONR10Rn, or R9 is CT-Cealkyl, C2-C6alkenyl, C2-C6alkanoyl, (C3-C7cyc to cyc) C0-C4alkyl, (C3-C7cycloalkenyl) Co-C4alkyl, ( C3-C7cycloalkyl) CH2S02-, (C3-C7cycloalkyl) CH2SO2NR10-, (C10-C4alkyl) heteroaryl, (Caryl) C0-C2alkyl, or (5-10 membered heteroaryl) Co-C2alkyl, each of which is optionally substituted; or R9 is a phosphonate of the formula wherein p is 0, 1, or 2. R9 is RxXC0-C4alkyl-, wherein X is - (C = 0) NH-, -NH (C = 0) - and Rx is aryl or heteroaryl, or R9 is -CH (RY) (C3-C7cycloalkyl), -S02CH (RY) (C3-C7cycloalkyl), or -NRi0SO2CH (RY) (C3-C7cycloalkyl), wherein RY is halogen or Rv is Ci-C6alkyl, C2-C6alkanoyl, (C3-C7cycloalkyl) Co-C4alkyl, (C -C7cycloalkenyl) C0-C4alkyl, (aryl) C0-Calkyl, (aryl) C0-C4alkoxy, (heterocycloalkyl) C0-C2alkyl, or (heteroaryl 5a 10 members) C0-C4alkyl, each of which is optionally substituted. River, Rii, and R12 independently are at each occurrence hydrogen, or C-i-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, (aryl) C0-C2alkyl, (C3-C7cycloalkyl) C0-C2alkyl, (C3-C7cycloalkenyl) Co-C2alkyl, (heterocycloalkyl) C0-C2alkyl, or (5- to 10-membered heteroaryl) C0-C2alkyl, each of which is optionally substituted; R13 is hydrogen or Ci-C2alkyl. R14 and R15 independently are hydrogen, hydroxyl, or Ci-C2alkyl; n is 0, 1, or 2; M is hydrogen, halogen, Ci-C2alkyl hydroxyl, or Ci-C2alkoxy. And it is absent, CR18Ri9, NR20, S, O, -O (C = O) (NR20) -, NH (C = O) (NR20) -, NH (S = O) (NR20) -, or -0 ( C = 0) -; or And it is taken together with one of J, L, or M to form a ring. J is CH2 or J is taken together with Y to form a carbocyclic or heterocyclic ring of 3 to 7 members, whose ring is substituted with 0 or 1 or more substituents independently selected from halogen, hydroxy, amino, cyano, C1-C2alkyl, C-i -C2alkoxy, C1-C2alkoxy, trifluoromethyl, and trifluoromethoxy; when J is taken together with Y to form a ring, Z may be absent. L is CH2 or L is taken together with Y to form a carbocyclic or heterocyclic ring of 3 to 7 members, which ring is substituted with 0 or 1 or more substituents independently selected from halogen, hydroxy, amino, cyano, C1 -C2alkoxy, C-C2alkoxy, trifluoromethyl, and trifluoromethoxy; when L is taken together with Y to form a ring, Z may be absent. Z is C0-C2alkyl or (mono- or bicyclic heteroaryl) C0-C2alkyl, each of which Z is substituted with 0 or 1 or more substituents independently selected from halogen, hydroxyl amino, cyano, -CON H2, -COOH, -S02NR1 1 R12, - d-Calkyl, C2-C4alkanoyl, CrC4alkoxy, CiC-alkylthio, mono- and di-C1-C4alkylamino, Ci- C4alkylester, C-C2haloalkyl, and C1-C2haloalkoxy, and 0 or 1 (C3-C7cycloalkyl) Co-C2alkyl , (phenyl) C0-C2alkyl, (phenyl) C0-C2alkoxy, (5- or 6-membered heteroaryl) C0-C2alkyl, (5- or 6-membered heteroaryl) C0-C2alkoxy, naphthyl, indanyl, (5- or 6-membered heterocycloalkyl) ) C0-C2alkyl, or 9 or 10 membered bicyclic heteroaryl, each of which is substituted with 0, 1, or 2 substituents independently selected from: (c) halogen, amino hydroxy, cyano, nitro, -COOH, - WITH H2, CH3 (C = 0) NH-, = NOH, d-C4alkyl, d-C4alcoxy, d-C4hydroxyalkyl > mono- and di-d-dalkylamino, -NR8S02Rii, - C (0) ORn, -NR8CORn, -NReCÍOJOR, trifluoromethyl, and trifluoromethoxy, and (d) phenyl and heteroaryl of 5 or 6 members, each of which is substituted with 0 or 1 or more of halogen, Ci-C4alkyl hydroxyl, and C1-C2alkoxy. R16 represents 0 to 4 substituents, is independently selected from halogen, C1-C2alkyl, and Ci-C2alkoxy. i8 and Ri9 independently are hydrogen, hydroxyl, halogen, d-dalkyl, d-C2alkoxy, d-dhaloalkyl, or Cr C2haloalkoxy. R2o is hydrogen, d-C2alkyl, C1-C2haloalkyl, or d-C2haloalkoxy. 2. A compound or salt of claim 1, further characterized in that R1 and R2 are joined to form a 5- to 7-membered heterocycloalkyl ring containing 1 or 2 heteroatoms independently selected from N, O, and S whose ring is optionally fused to a 5 or 6 membered phenyl or heteroaryl to form a bicyclic ring system, each of which 5- to 7-membered heterocycloalkyl ring or bicyclic ring system is optionally substituted. 3. A compound or salt of claim 2, further characterized in that R1 and R2 are joined to form a pyrrolidine ring, piperidine or piperazine or a piperazine ring fused with a phenyl, each of which is optionally substituted with 0 to 2 substituents independently selected from halogen, hydroxy lo, amino, CONH2, -COOH, d-Czalkyl, and d -C2alcoxy. 4. A compound of claim 1, wherein Ri is d - C40 (C = 0) -, d - d (C = 0) - 5. A compound or salt of Figure 4, further characterized in that R2 is Ci-C6alkyl or C3-C7cycloalkyl. 6. A compound or salt of claim 4, further characterized in that R2 is hydrogen. 7. A compound or salt of any of the claims 1 through 6, further characterized in that R3 and R4 independently are (a) hydrogen, or (b) C1-C4alkyl or (C3-C7cycloalkyl) C0-C alkyl, each of which is substituted with 0 to 3 substituents independently selected from halogen, hydroxyl amino, cyano, -CONH2, -COOH, Ci-C4alkyl, C2-C4alkanoyl, d-C4aicoxy, Ci-C4alkylthio, mono- and di-C-C4alkylamino, C1-C2haloalkyl, and C -C2haloalkoxy. 8. A compound or salt of claim 7, further characterized in that R3 and R4 independently are hydrogen, C-C4alkyl, or (C3-C7cycloalkyl) Co-C alkyl. 9. A compound or salt of claim 8, further characterized in that R3 and R4 are independently hydrogen or methyl. 1 0. A compound or salt of any of the claims1 through 6, further characterized in that R3 and R4 are linked to form a 3- to 7-membered cycloalkyl ring or a 3- to 7-membered heterocycloalkyl ring containing 1 or 2 heteroatoms independently selected from N, S, and O, each of said rings is substituted with 0 to 2 substituents independently selected from halogen, hydroxyl amino, cyano, vinyl, Ci-C2alkyl, C-) -C2alkoxy, trifluoromethyl, and trifluoromethoxy. eleven . A compound or salt of claim 10, further characterized in that R3 and R4 are joined to form a 3- to 7-membered cycloalkyl ring or a 5-6 membered heterocycloalkyl ring containing 1 or 2 heteroatoms independently selected from N, S, and O, each of said rings being substituted with 0 to 2 substituents independently selected from halogen, hydroxyl, C! . 2. A compound or salt of any of claims 1 to 11, further characterized in that R5 and R6 independently are (a) hydrogen, or (b) C-C4alkyl or (C3-C7cycloalkyl) Co-C4alkyl, each of which is substituted with 0 to 3 substituents independently selected from halogen, amino hydroxy, cyano, -CON H2, -COOH, CT-C-alkyl, C2-C4alkanoyl, C-C4alkoxy, C1-C4alkylthio, mono- and di-C1- C4alkylamino, C1-C2haloalkyl, and C1-C2haloalkoxy. 13. A compound or salt of claim 12, further characterized in that R5 and R6 are independently hydrogen, CTdalkyl, or (C3-C7cycloalkyl) Co-C4alkyl. 4. A compound or salt of claim 13, further characterized in that R5 and R6 independently are hydrogen or methyl. 5. A compound or salt of any of claims 1 to 11, further characterized in that R5 and R6 are linked to form a 3- to 7-membered cycloalkyl ring or a 3-7 membered heterocycloalkyl ring which contains 1 or 2 heteroatoms independently selected from N, S, and O, each of said rings is substituted with 0 to 2 substituents independently selected from halogen, hydroxyl amino, cyano, vinyl, C 1 -C 2 alkyl, C -C 2 alkoxy, trifiuoromethyl, and trifluoromethoxy. 1 6. A compound or salt of claim 1, further characterized in that R5 and Re are linked to form a 3 to 7 membered cycloalkyl ring or a 5-6 membered heterocycloalkyl ring containing 1 or 2 heteroatoms independently selected from N , S, and O, each of said rings is substituted with 0 to 2 substituents independently selected from halogen, hydroxyl, C ^ C ^ alkyl, and Ci-C2alkoxy. 7. A compound or salt of any of claims 1 to 16, further characterized in that R7 and R8 independently are (a) hydrogen, or (b) C i -C4alkyl or (C3-C7cycloalkyl) Co-C4alkyl, each one of which is substituted with 0 to 3 substituents independently selected from halogen, amino hydroxy, cyano, -CON H2, -COOH, d-C4alkyl, C2-C4alkanoyl, C1-C4alkoxy, C-C4alkylthio, mono- and di-C 1 -C4alkylamino, Ci -C2haloalkyl, and Ci -C2haloalkoxy. 1 8. A compound or salt of claim 1 7, further characterized in that R7 and R8 are independently hydrogen, C4-C4alkyl, or (C3-C7cycloalkyl) Co-C4alkyl. 19. A compound or salt of claim 18, further characterized in that R7 and R8 are independently hydrogen or methyl. 20. A compound or salt of any of the claims 1 to 16, further characterized in that R7 and R8 are joined to form a 3- to 7-membered cycloalkyl ring or 3-7 membered heterocycloalkyl ring containing 1 or 2 heteroatoms independently selected from N, S, and O, each of said rings is substituted with 0 to 2 substituents independently selected from halogen, hydroxyl amino, cyano, vinyl, C! -Caalkyl, C-C2alkoxy, trifluoromethyl, and trifluoromethoxy. 21. A compound or salt of claim 20, further characterized in that R7 and R8 are joined to form a 3- to 7-membered cycloalkyl ring or a 5- to 6-membered heterocycloalkyl ring containing 1 or 2 heteroatoms independently selected from N, S, and O, each of said rings is substituted with 0 to 2 substituents independently selected from halogen, hydroxyl, C! ^ Alkyl, and d-Caalkoxy. 22. A compound or salt of any of claims 1 to 6 further characterized in that R3, R4, and R6, independently are hydrogen or methyl; R5 is Ci-C6alkyl, C2-C6alkenyl, (C3-C7cycloalkyl) C0- C4alkyl, (C3-C7cycloalkenyl) C0-C4alkyl, (heterocycloalkyl) C0-C4alkyl, C2-C6alkanoyl, or mono- or di-d-Cealkylamino; and R7 and R8 are joined to form an optionally substituted 3 to 7-membered cycloalkyl ring or an optionally substituted 3 to 7 membered heterocycloalkyl ring, containing 1 or 2 heteroatoms independently selected from N, S, and O. 23. A compound or salt of claim 19, further characterized in that R5 is d-Cealkyl or (C3-C7cycloalkyl) C0-C4alkyl; and R7 and R8 are joined to form a cyclopropyl ring, which is unsubstituted or is substituted with 1 or 2 d-C6alkyl or C2-C6alkenyl. 24. A compound or salt of claim 20, of the formula: 25. A compound or salt of any of the claims I to 6, further characterized in that R3. R4, R6 and e independently are hydrogen or methyl; and R5 is a saturated or unsaturated hydrocarbon chain of 7 to II carbon atoms which is covalently attached to R7, wherein R7 is a methylene group. 26. A compound or salt of claim 25, of the formula z wherein D is an alkyl or alkenyl group having 6 to 10 carbon atoms. 27. A compound or salt of claim 26, of the formula 28. A compound or salt of any of the claims I to 6, further characterized in that R3. R4, and R6 independently are hydrogen or methyl; and R5 is a saturated or unsaturated hydrocarbon chain of 7 to II carbon atoms which is covalently linked to an optionally substituted cycloalkyl ring, formed by R7 and R8 which are bonded to form a 3- to 7-membered cycloalkyl ring optionally substituted. 29. A compound or salt of claim 28, of the formula wherein D is an alkyl or alkenyl group having 6 to 10 carbon atoms. 30. A compound or salt of claim 29, of the formula 31. A compound or salt of any of claims 1 to 30, further characterized in that T is a group of the formula R9 is hydroxyl, amino, -COOH, -NR10R, -OR-12, -SR12, -NR10 (S = O) R, -NR10SO2Rii, -NRTOSONRUR ^, -NR10SO2NR1, R12, - (C = O) OR10, - NR10 (C = O) OR, or - CONR10R. 32. A compound or salt of claim 31, further characterized in that R9 is -NR10SO2R. 33. A compound or salt of claim 32, further characterized in that RN0 is hydrogen or methyl and R1¾ is cyclopropyl. 34. A compound or salt of claim 31, further characterized in that R9 is hydroxyl, amino, -COOH, -NR10R, -OR12, -NR10SO2R11, - (C = O) OR10, or -CONR10R- 35. A compound or salt of any of claims 1 to 30, further characterized in that T is a group of the formula R9 is d-Cealkyl, C2-C6alkenyl, C2-C6alkanoyl, (C3-C7cycloalkyl) Co-C4alkyl, (C3-C7cycloalkenyl) C0-Calkyl, (heterocycloalkyl) Co-C4alkyl, (arid) C0 -C2alkyl, or (5- to 10-membered heteroaryl) Co-C2alkyl, each of which is substituted with 0 or 1 or more substituents independently selected from halogen, hydroxyl, amino, cyano, oxo -COOH, -CONH2, oxo, C -C4alkyl, C2-C4alkanoyl, C1-C alkylthio, mono- and diCiCalkylamino, dC4alkyl ester, mono- and diC-C4alkylcarboxamide, C1-C2haloalkyl, and Ci-C2haloalkoxy. 36. A compound or salt of claim 35, further characterized in that R9 is Ci-C6alkyl, C2-C6alkenyl, C2-C6alkanoyl, (C3-C7cycloalkyl) C0-Calkyl, (C3-C7cycloalkenyl) C0-C4alkylO, ( heterocycloalkyl) C0-C4alkyl, (aryl) C0-C2alkyl, or (C10-C2alkyl heteroaryl), each of which is substituted with 0 or 1 or more substituents independently selected from halogen, hydroxyl amino, cyano, oxo -COOH, -CONH2, C1-C4alkyl, C-C4alkoxy, mono- and di- Ci-C4alkylamino, C1-C2haloalkyl, and Ci-C2haloalcoxL 37. A compound or salt of any of claims 1 to 30, further characterized in that R9 is a phosphonate of the formula wherein p is 1 or 2. 38. A compound or salt of any of claims 1 to 30, further characterized in that: R9 is RxXC1-C4alkyl-, wherein X is - (C = 0) NH-, -NH ( C = 0) - and Rx is phenyl or pyridyl. 39. A compound or salt of any of claims 1 to 30, further characterized in that: R9 is -CH (RY) (C3-C7cycloalkyl), -S02CH (RY) (C3-C7cycloalkyl), or -NR10SO2CH (RY) ( C3-C7cycloalkyl), wherein RY is halogen, or RY is Ci-C2alkyl, C2-C6alkanoyl, (C3-C7cycloalkyl) C0-C2alkyl, (phenyl) C0-C alkyl, (phenyl) C0-C4alkoxy, (heterocycloalkyl) C0 -C2alkyl, or (5- to 10-membered heteroaryl) C0-C4alkyl, each of which is substituted with 0 or 1 or more substituents independently selected from halogen; hydroxyl, amino, cyano, oxo -COOH, -CONH2, oxo, C1-C4alkyl, C1-C4alkoxy, mono- and di-C1-C4alkylamino, C! -Caalkalkyl, and C1-C2haloalkoxy. 40. A compound of any of claims 1 to 39 further characterized in that River. R11 and R12 independently are Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C7cycloalkyl) Co-C4alkyl, (heterocycloalkyl) C0-C alkyl, (C phenyl) C0-C2alkyl, (naphthyl) C0-C2alkyl, or (C10-C2) heteroaryl (heteroaryl), each of which is substituted with 0 to 3 substituents independently selected from halogen, hydroxyl amino, cyano, oxo -COOH, -CONH2) oxo, C1-C4alkyl, Ci-C4alkoxy, C2-C4alkanoyl, dC alkylthio, mono- and di- C1-C4alkylamino, C1-C4alkylester, mono- and di- C1 -C4alkylcarboxamide, C1-C2haloalkyl and C ^ -C ^ haloalkoxy. 41. A compound or salt of claim 40, further characterized in that R-io. R11 and R12 independently are hydrogen, or Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C7cycloalkyl) C0-C2alkyl, (heterocycloalkyl) C0-C2alkyl, (phenyl) C0-C2alkyl, or (monocyclic heteroaryl 5a 6 members) C0-C2alkyl, each of which is substituted with 0 to 3 substituents independently selected from halogen, hydroxyl oxo, C1-C2alkyl, Ci-C2alkoxy, trifluoromethyl, and trifluoromethoxy. 42. A compound or salt of claim 40, further characterized in that Rio, R and Ri2 independently are hydrogen or C! -Cealkyl. 43. A compound or salt of any of claims 1 to 42, further characterized in that n is 0; and Y is absent, is CH2, O, or is -0 (C = 0) -. 44. A compound or salt of claim 40 further characterized in that n is 0 and Y is O. 45. A compound or salt of any of claims 1 to 42 further characterized in that n is; And it is absent, is CH2, O, or is -0 (C = 0) -; and R e and R 1 9 independently are hydrogen or methyl. 46. A compound or salt of any of claims 1 to 45, further characterized in that M is hydrogen. 47. A compound or salt of any of claims 1 to 46, further characterized in that J and L are both CH2. 48. A compound or salt of any of claims 1 to 47, further characterized in that Z is 1-naphthyl, 2-naphthyl, 49. A compound or salt of any of claims 1 to 47, further characterized in that Z is a group of the formula further characterized because X-i, 2 > X3 4 and 5 independently are N or CH and not more than two of X ^ - X5 are N. Gi, G2, G3, and G4 independently are CH2, O, S, or NR26, where no more than two from G1 to G4 they are different from hydrogen. R2i represents from 0 to 3 groups independently selected from halogen, amino hydroxy, cyano, -CONH2, -COOH, C1-C4alkyl, C2-C4alkanoyl, Ci-C4alkoxy, C1-C4alkylthio, mono- and di-d-Ctalkylamino, C1- C2haloalkyl, and Ci-C2haloalkoxy. R22 is hydrogen, halogen, amino hydroxy, cyano, -CONH2, -COOH, C1-C4alkyl, C2-C alkanoyl, C1-C4alkoxy, d-Calkylthio, mono- and di-Ci-C4alkylamino, C1-C4alkylester, Ci-C2haloalkyl, and C1-C2haloalkoxy, or R22 is (C3-C7cycloalkyl) C0-C2alkyl, (phenyl) C0-C2alkyl, (phenol) C0 -C2alkoxy, (5- or 6-membered heteroaryl) Co-C2alkyl, (5-6 membered heteroaryl) C0-C2alkoxy, naphthyl, indanyl, (5- or 6-membered heterocycloalkyl) C0-C2alkyl, or 0- or 10-membered bicyclic heteroaryl, each of which is substituted with 0, 1, or 2 substituents independently selected from (c) gen, amino hydroxy, cyano, nitro, -COOH, -CONH2, CH3 (C = 0) NH-, Ci-C4alkyl, Ci-C4alkoxy, C! -dydroxyalkyl, mono- and di- -C1-C4alkylamino, -NR8S02R1i, -C (0) OR, -NRaCORn, -NR8C (0) ORii, trifluoromethyl, trifluoromethoxy, and (d) phenyl and heteroaryl of 5 or 6 members, each of which is substituted with 0 or 1 or more of gen, hydroxyl, C 4 -C 4 alkyl, Ci-C 2 alkoxy. R23 is 0 to 2 substituents independently selected from gen, Ci-C2alkyl hydroxyl, and Ci-C2alkoxy. R24 is independently selected at each occurrence between hydrogen and C-C2alkyl. 50. A compound or salt of claim 49, further characterized in that R22 is -OCH2CH3. 51. A compound or salt of claim 49, wherein Z is a group of the formula further characterized because ?? 2. X3, and X4, independently are N or CH and not more than R21 represents from 0 to 3 groups independently selected from halogen, hydroxyl amino, cyano, -CONH2, - COOH, C1-C4alkyl, - C2-C4alkanoyl, d-C4alkoxy, Ci-C4alkylthio, mono- and di-d-C alkylamino, Ci-C2haloalkyl, and C1-C2haloalkoxy. R22 is hydrogen, halogen, hydroxyl, amino, cyano, -CONH2, -COOH, dC alkyl, C2-C4alkanoyl, d-Calkoxy, Ci-C4alkylthio, mono- and di-C-C4alkylamino, Ci-C4alkylster, C1-C2haloalkyl, and d-C2haloalcox; or R22 is (C3-C7cycloalkyl) Co-C2alkyl, (phenyl) C0-C2alkyl, (phenyl) C0-C2alkoxy, (5- or 6-membered heteroaryl) C0-C2alkyl, (5- or 6-membered heteroaryl) C0-C2alkoxy, naphthyl, indanyl, (5- or 6-membered heterocycloalkyl) C0-C2alkyl, or 0- or 10-membered bicyclic heteroaryl, each of which is substituted with 0, 1, or 2 substituents independently selected from (c) halogen, amino hydroxy , cyano, nitro, -COOH, -CONH2I CH3 (C = 0) NH-, C1-C alkyl, C1-C alkoxy, d-C4hydroxyalkyl, mono- and di-d-C4alkylamino, -NR8S02R, -C (0) OR, -NR8CORn, -NReCOCHORn, trifluoromethyl, and trifluoromethoxy, and (d) phenyl and 5- or 6-membered heteroaryl, each of which is substituted with 0 or 1 or more of halogen, hydroxyl dC alkyl, d-C2alkoxy. 52. A compound or salt of claim 51, further characterized in that Z is a group of the formula 53. A compound or salt of claim 51, wherein Z is a quinoline of the formula 54. A compound or salt of claim 53, further characterized in that R21 represents a substituent at the 7 position of the quinoline, and 0 to 2 additional substituents independently selected from halogen, hydroxyl, amino, cyano, -CON H2, -COOH, C1- C4alkyl, C2-C alkanoyl, d -Calkoxy, mono- and di-CT -CAalkylamino, C1-C2haloalkyl, and C1-C2haloalkoxy; and R22 is (phenyl) C0-C2alkyl or C0-C2alkyl (pyridyl) alkyl, each of which is substituted with 0, 1, or 2 substituents independently selected from halogen, hydroxyl, amino, cyano, -COOH, -CONH2, Ci -C4alkyl, C1-C4alkoxy, mono- and di-Ci-C4alkylamino, trifluoromethyl, and trifluoromethoxy. 55. A compound or salt of claim 53, further characterized in that R2i is a methoxy or ethoxy substituent at the 7-position of the quinoline and R22 is phenyl or pyridyl. 56. A compound or salt of any of claims 1 to 47, further characterized in that n is 0, Z is absent, and Y and M are taken together to form a ring, such that Gi, G2, G3, G4, and G5 independently are CH2, O, S, or N R22; further characterized in that no more than two of G f G2, G3, G4, and G5 are other than CH2; R21 is 0 to 2 substituents independently selected from halogen, hydroxy, Ci-C2alkyl, and Ci-C2alkoxy; R22 is independently selected at each occurrence between hydrogen and methyl; and R23 is 0 to 2 substituents independently selected from halogen, hydroxy, C1-C2alkyl, and C-i-C2alcoxy. 57. A compound or salt of claim 1 to 47 further characterized in that n is 0, M is hydrogen, Z is absent, and Y and J are taken together to form a ring, such that it's a group for the formula: Gi, G2, G3 and G4 independently are CH2, O, S, or NR22; further characterized in that no more than two of G t G 2, G 3 and G 4 are other than CH 2; R2i is 0 to 2 substituents independently selected from halogen, hydroxy, C-C2alkyl, and C ^ -C2alkoxy; R22 is 0 to 2 substituents independently selected from halogen, hydroxy, C-C2alkyl, and C ^ -C ^ alkoxy; and R23 is 0 to 2 substituents independently selected from halogen, hydroxy, C-C2alkyl, and C1-C2alkoxy. 58. A compound or salt of claim 57, further characterized in that it's a group for the formula: 59. A compound or salt of any of claims 1 to 47, further characterized in that n is 0, Z is absent, and Y and L are taken together to form a ring, such that it's a group for the formula: where: G-? , G2 l G3, and G4 independently are CH2 > O, S, or N R22; further characterized in that no more than two of G G2, G3, and G4 are other than CH2; Q1 and Q2 independently are CH or N; R21 is 0 to 2 substituents independently selected from halogen, hydroxy, Ci-C2alkyl, and Ci-C2alkoxy; R22 is 0 to 2 substituents independently selected from halogen, hydroxy, d-C2alkyl, and Ci-C2alkoxy; and R23 is 0 to 2 substituents independently selected from halogen, hydroxy, Ci-C2alkyl, and Ci-C2alkoxy. 60. A compound or salt of claim 59, further characterized in that it's a group for the formula: . A compound or salt of claim 1, of the formula further characterized in that Ri and R2 are attached to form a pyrrolidine, piperidine or piperazine ring or a piperazine ring fused with a phenyl, each of which is optionally substituted with 0 to 2 substituents independently selected from halogen, amino hydroxyl, CONH2, C1 -C4alkyl (C = 0) -COOH, d-Czalkyl, and Ci-C2alkoxy; R3, R4, R5 and R6 independently are selected from hydrogen, C1-C4alkyl, and (C3-C7cycloalkyl) C0-C2alkyl; R9 is hydroxyl, amino, -COOH, -NR10Rn, -OR12, - (C = O) OR1 0, or -CON R R10. R11 and R12 independently are hydrogen, or Ci-Cealkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C7cycloalkyl) Co-C2alkyl, (heterocycloalkyl) C0-C2alkyl, (phenyl) C0-C2alkyl, or (monocyclic heteroaryl 5a 6 members) C0-C2alkyl, each of which is substituted with 0 to 3 substituents independently selected from halogen, hydroxyl oxo, C1-C2alkyl, C-C2alkoxy, trifluoromethyl, and trifluoromethoxy; R16 is 0 to 2 substituents independently selected from halogen, and C1-C2alkoxy; M is hydrogen or methyl; and Z is a quinoline of the formula wherein R2i represents a substituent at the 7 position of the quinoline, and 0 to 2 additional substituents independently selected from halogen, amino hydroxy, cyano, -CON H2, -COOH, Ci-C4alkyl, C2-C4alkanoyl, C1-C4alkoxy, mono - and di-C -C4alkylamino, C1-C2haloalkyl, and C1-C2haloalkoxy; and R22 is (C02) C0-C2alkyl or (C3-C2-C2) alkyl, each of which is substituted with 0, 1, or 2 substituents selected independently of halogen, hydroxyl amino, cyano, -COOH, - CONH2, C1-C4alkyl, mono- and di-C1-C4alkylamino, thiifluoromethyl, and trifluoromethoxy. 62. A pharmaceutical composition containing a therapeutically effective amount of one or more compounds or salts of any of claims 1 to 61 and at least one pharmaceutically acceptable carrier. 63. The pharmaceutical composition of claim 62, which additionally contains a second active agent. 64. The pharmaceutical composition of claim 63, further characterized in that the second active agent is ribavarin. 65. The pharmaceutical composition of any one of claims 62 to 64, which additionally contains at least one interferon or conjugate Peg-interferon alpha. 66. The pharmaceutical composition of any of claims 62 to 65, further characterized in that the composition is formulated as an injectable fluid, an aerosol, a cream, a gel, a tablet, a pill, a capsule, a syrup, an ophthalmic solution , or a transdermal patch. 67. A package containing the pharmaceutical composition of any of claims 60 to 66 in a container and further including instructions for using the composition to treat a patient suffering from Hepatitis C infection. 68. A method for treating or preventing a Hepatitis C infection, which comprises providing a therapeutically effective amount of one or more compounds of any of the claims 1 to 61 to a patient in need thereof. 69. The method of claim 66, further characterized in that the therapeutically effective amount is an amount sufficient to significantly decrease the amount of HCV antibodies in the serum or blood of the patient. 70. A method for inhibiting HCV replication in vivo which comprises providing an HCV-infected patient with a concentration of a compound or salt of any one of claims 1 to 61 sufficient to inhibit replication of the HCV replicon in vitro.